Role of fibroblast growth factor receptor signaling in kidney development.
Bates Carlton M
American journal of physiology. Renal physiology
Fibroblast growth factor receptors (Fgfrs) consist of four signaling family members and one nonsignaling "decoy" receptor, Fgfr-like 1 (Fgfrl1), all of which are expressed in the developing kidney. Several studies have shown that exogenous fibroblast growth factors (Fgfs) affect growth and maturation of the metanephric mesenchyme (MM) and ureteric bud (UB) in cultured tissues. Transgenic and conditional knockout approaches in whole animals have shown that Fgfr1 and Fgfr2 (predominantly the IIIc isoform) in kidney mesenchyme are critical for early MM and UB formation. Conditional deletion of the ligand, Fgf8, in nephron precursors or global deletion of Fgfrl1 interrupts nephron formation. Fgfr2 (likely the IIIb isoform signaling downstream of Fgf7 and Fgf10) is critical for ureteric morphogenesis. Moreover, Fgfr2 appears to act independently of Frs2α (the major signaling adapter for Fgfrs) in regulating UB branching. Loss of Fgfr2 in the MM leads to many kidney and urinary tract anomalies, including vesicoureteral reflux. Thus Fgfr signaling is critical for patterning of virtually all renal lineages at early and later stages of development.
Role of fibroblast growth factor receptor signaling in kidney development.
Bates Carlton M
Pediatric nephrology (Berlin, Germany)
Fibroblast growth factor receptors (Fgfrs) are expressed throughout the developing kidney. Several early studies have shown that exogenous fibroblast growth factors (Fgfs) affect growth and maturation of the metanephric mesenchyme (MM) and ureteric bud (UB). Transgenic mice that over-express a dominant negative receptor isoform develop renal aplasia/severe dysplasia, confirming the importance of Fgfrs in renal development. Furthermore, global deletion of Fgf7, Fgf10, and Fgfr2IIIb (isoform that binds Fgf7 and Fgf10) in mice leads to small kidneys with fewer collecting ducts and nephrons. Deletion of Fgfrl1, a receptor lacking intracellular signaling domains, causes severe renal dysgenesis. Conditional targeting of Fgf8 from the MM interrupts nephron formation. Deletion of Fgfr2 from the UB results in severe ureteric branching and stromal mesenchymal defects, although loss of Frs2α (major signaling adapter for Fgfrs) in the UB causes only mild renal hypoplasia. Deletion of both Fgfr1 and Fgfr2 in the MM results in renal aplasia with defects in MM formation and initial UB elongation and branching. Loss of Fgfr2 in the MM leads to many renal and urinary tract anomalies as well as vesicoureteral reflux. Thus, Fgfr signaling is critical for patterning of virtually all renal lineages at early and later stages of development.
The role of chronic inflammation in cutaneous fibrosis: fibroblast growth factor receptor deficiency in keratinocytes as an example.
Meyer Michael,Müller Anna-Katharina,Yang Jingxuan,Ŝulcová Jitka,Werner Sabine
The journal of investigative dermatology. Symposium proceedings
Fibrosis is associated with a variety of skin diseases and causes severe aesthetic and functional impairments. Functional studies in rodents, together with clinical observations, strongly suggest a crucial role of chronic injury and inflammation in the pathogenesis of fibrotic diseases. The phenotype of mice lacking fibroblast growth factor (FGF) receptors 1 and 2 in keratinocytes supports this concept. In these mice, a defect in keratinocytes alone initiated an inflammatory response, which in turn caused keratinocyte hyperproliferation and dermal fibrosis. As the mechanism underlying this phenotype, we identified a loss of FGF-induced expression of claudins and occludin, which caused abnormalities in tight junctions with concomitant deficits in epidermal barrier function. This resulted in severe transepidermal water loss and skin dryness. In turn, activation of keratinocytes and epidermal γδ T cells occurred, which produced IL-1 family member 8 and S100A8 and S100A9. These cytokines attracted immune cells and activated fibroblasts, resulting in a double paracrine loop through production of keratinocyte mitogens by dermal cells. In addition, a profibrotic response was induced in fibroblasts. Our results highlight the importance of an intact epidermal barrier for the prevention of inflammation and fibrosis and the role of chronic inflammation in the pathogenesis of fibrotic diseases.
Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias.
Foldynova-Trantirkova Silvie,Wilcox William R,Krejci Pavel
In 1994, the field of bone biology was significantly advanced by the discovery that activating mutations in the fibroblast growth factor receptor 3 (FGFR3) receptor tyrosine kinase (TK) account for the common genetic form of dwarfism in humans, achondroplasia (ACH). Other conditions soon followed, with the list of human disorders caused by FGFR3 mutations now reaching at least 10. An array of vastly different diagnoses is caused by similar mutations in FGFR3, including syndromes affecting skeletal development (hypochondroplasia [HCH], ACH, thanatophoric dysplasia [TD]), skin (epidermal nevi, seborrhaeic keratosis, acanthosis nigricans), and cancer (multiple myeloma [MM], prostate and bladder carcinoma, seminoma). Despite many years of research, several aspects of FGFR3 function in disease remain obscure or controversial. As FGFR3-related skeletal dysplasias are caused by growth attenuation of the cartilage, chondrocytes appear to be unique in their response to FGFR3 activation. However, the reasons why FGFR3 inhibits chondrocyte growth while causing excessive cellular proliferation in cancer are not clear. Likewise, the full spectrum of molecular events by which FGFR3 mediates its signaling is just beginning to emerge. This article describes the challenging journey to unravel the mechanisms of FGFR3 function in skeletal dysplasias, the extraordinary cellular manifestations of FGFR3 signaling in chondrocytes, and finally, the progress toward therapy for ACH and cancer.
Adding to the mix: fibroblast growth factor and platelet-derived growth factor receptor pathways as targets in non-small cell lung cancer.
Kono S A,Heasley L E,Doebele R C,Camidge D R
Current cancer drug targets
The treatment of advanced non � small cell lung cancer (NSCLC) increasingly involves the use of molecularly targeted therapy with activity against either the tumor directly, or indirectly, through activity against host-derived mechanisms of tumor support such as angiogenesis. The most well studied signaling pathway associated with angiogenesis is the vascular endothelial growth factor (VEGF) pathway, and the only antiangiogenic agent currently approved for the treatment of NSCLC is bevacizumab, an antibody targeted against VEGF. More recently, preclinical data supporting the role of fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR) signaling in angiogenesis have been reported. The platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) pathways may also stimulate tumor growth directly through activation of downstream mitogenic signaling cascades. In addition, 1 or both of these pathways have been associated with resistance to agents targeting the epidermal growth factor receptor (EGFR) and VEGF. A number of agents that target FGF and/or PDGF signaling are now in development for the treatment of NSCLC. This review will summarize the potential molecular roles of PDGFR and FGFR in tumor growth and angiogenesis, as well as discuss the current clinical status of PDGFR and FGFR inhibitors in clinical development.
Importance of fibroblast growth factor receptor in neovascularization and tumor escape from antiangiogenic therapy.
Saylor Philip J,Escudier Bernard,Michaelson M Dror
Clinical genitourinary cancer
Therapeutic inhibition of pathways involved in angiogenesis has become the standard of care in renal cell carcinoma (RCC). Most currently available antiangiogenic agents inhibit the vascular endothelial growth factor (VEGF) pathway. Although these drugs have produced exciting benefits, some tumors do not respond to these agents. In addition most if not all tumors that initially respond will eventually develop resistance. Tumor escape from antiangiogenic therapy may include various signaling pathways that are involved in angiogenesis, including the fibroblast growth factor (FGF) signaling pathway. Emerging preclinical data suggest that FGF and VEGF act distinctly and synergistically to promote tumor vascularization. The current review discusses the role of FGF signaling in resistance to anti-VEGF therapies and outlines potential therapeutic implications.
Syndromic craniosynostosis, fibroblast growth factor receptor 2 (FGFR2) mutations, and sacrococcygeal eversion presenting as human tails.
Wilkinson C Corbett,Manchester David K,Keating Robert F,Ketch Lawrence L,Winston Ken R
Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery
INTRODUCTION:There have been 23 previously published cases of patients with syndromic craniosynostosis and human tails. In many of these, the tail was composed of prominent coccygeal and sacral vertebrae, curved in a retroverted instead of in the normal anterograde fashion. This has been termed sacrococcygeal eversion. In those cases in which genetic testing results are reported, there were fibroblast growth factor receptor 2 (FGFR2) mutations. METHODS:We present three patients with Pfeiffer syndrome and sacrococcygeal eversion. Two had genetic testing and both had FGFR2 mutations, one of them a novel mutation in patients with syndromic craniosynostosis and sacrococcygeal eversion. We also briefly review the literature on craniosynostosis and human tails. RESULTS:All but one reported patient has had either Pfeiffer, Crouzon, or Beare-Stevenson syndrome. Most patients, including ours, have had severe manifestations of their syndrome. Although the pathogenesis of sacrococcygeal eversion is unknown, a similarly posteriorly curved tail bud develops in normal human embryos during the second month of gestation. CONCLUSIONS:Perhaps increased FGFR2 activation during this embryonic period leads to abnormal differentiation or regression of the tail bud and, in turn, sacrococcygeal eversion, in certain patients with severe syndromic craniosynostosis.
Fibroblast growth factor receptor inhibitors.
Kumar Suneel B V S,Narasu Lakshmi,Gundla Rambabu,Dayam Raveendra,J A R P Sarma
Current pharmaceutical design
Fibroblast growth factor receptors (FGFRs) play an important role in embryonic development, angiogenesis, wound healing, cell proliferation and differentiation. The fibroblast growth factor receptor (FGFR) isoforms have been under intense scrutiny for effective anticancer drug candidates. The fibroblast growth factor (FGF) and its receptor (FGFR) provide another pathway that seems critical to monitoring angiogenesis. Recent findings suggest that FGFR mediates signaling, regulates the PKM2 activity, and plays a crucial role in cancer metabolism. The current review also covers the recent findings on the role of FGFR1 in cancer metabolism. This paper reviews the progress, mechanism, and binding modes of recently known kinase inhibitors such as PD173074, SU series and other inhibitors still under clinical development. Some of the structural classes that will be highlighted in this review include Pyrido[2,3-d]pyrimidines, Indolin- 2-one, Pyrrolo[2,1-f][1,2,4]triazine, Pyrido[2,3-d]pyrimidin-7(8H)-one, and 1,6- Naphthyridin-2(1H)-ones.
Fibroblast growth factor receptor inhibitors as a cancer treatment: from a biologic rationale to medical perspectives.
Dieci Maria Vittoria,Arnedos Monica,Andre Fabrice,Soria Jean Charles
The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway plays a fundamental role in many physiologic processes, including embryogenesis, adult tissue homeostasis, and wound healing, by orchestrating angiogenesis. Ligand-independent and ligand-dependent activation have been implicated in a broad range of human malignancies and promote cancer progression in tumors driven by FGF/FGFR oncogenic mutations or amplifications, tumor neoangiogenesis, and targeted treatment resistance, thereby supporting a strong rationale for anti-FGF/FGFR agent development. Efforts are being pursued to develop selective approaches for use against this pathway by optimizing the management of emerging, class-specific toxicity profiles and correctly designing clinical trials to address these different issues.
Fibroblast growth factor receptor-3 in urothelial tumorigenesis.
Iyer Gopa,Milowsky Matthew I
Fibroblast growth factor receptor-3 (FGFR3) is a receptor tyrosine kinase implicated in the tumorigenesis of multiple malignancies, including bladder and other urothelial cancers, multiple myeloma, and cervical cancer. In urothelial carcinoma (UC), constitutive receptor activation occurs most commonly through substitution of a wild-type residue with cysteine in the extracellular domain of FGFR3, thereby resulting in dimerization (through disulfide bridge formation) and subsequent stimulation of tyrosine kinase activity. Activating mutations of FGFR3 have been observed in up to 70% of non-muscle-invasive bladder tumors, while overexpression of a wild-type receptor, found in approximately 40% of tumors, has been correlated with more invasive disease. The identification of FGFR3 mutations in UC has sparked substantial interest in the therapeutic exploitation of these aberrations, and in vitro studies have provided evidence that such alterations may represent driver oncogenic lesions. In this review, we discuss the biologic and prognostic impact of FGFR3 mutations in UC as well as FGFR3 as a potential target for novel therapeutics.
Oncogenic role of fibroblast growth factor receptor 3 in tumorigenesis of urinary bladder cancer.
Pandith Arshad A,Shah Zafar A,Siddiqi Mushtaq A
Bladder cancer is the second most common genitourinary tumor and constitutes a very heterogeneous disease. Molecular and pathologic studies suggest that low-grade noninvasive and high-grade invasive urothelial cell carcinoma (UCC) arise via distinct pathways. Low-grade noninvasive UCC represent the majority of tumors at presentation. A high proportion of patients with low-grade UCC develop recurrences but usually with no progression to invasive disease. At presentation, a majority of the bladder tumors (70%-80%) are low-grade noninvasive (pTa). Several genetic changes may occur in bladder cancer, but activating mutations in the fibroblast growth factor receptor 3 (FGFR3) genes are the most common and most specific genetic abnormality in bladder cancer. Interestingly, these mutations are associated with bladder tumors of low stage and grade, which makes the FGFR3 mutation the first marker that can be used for diagnosis of noninvasive bladder tumors. Since the first report of FGFR3 involvement in bladder tumors, numerous studies have been conducted to understand its function and thereby confirm the oncogenic role of this receptor particularly in noninvasive groups. Efforts are on to exploit this receptor as a therapeutic target, which holds much promise in the treatment of bladder cancer, particularly low-grade noninvasive tumors. Further studies need to explore the potential use of FGFR3 mutations in bladder cancer diagnosis, prognosis, and in surveillance of patients with bladder cancer. This review focuses on the role of FGFR3 in bladder tumors in the backdrop of various studies published.
[Advanced research of fibroblast growth factor receptor in non-small cell lung cancer].
Pu Dan,Hou Mei
Zhongguo fei ai za zhi = Chinese journal of lung cancer
Lung cancer is severely threatening human health. In recent years, the treatment for lung adenocarcinoma has made a great progress, targeted therapy has been widely applied in clinic, and benefits amount of patients. However, in squamous cell lung cancer, the incidence of epidermal growth factor receptor (EGFR) gene mutant and ALK fusion gene are low,and targeted therapy like Tarceva and crizotinib, can hardly work. Since the fibroblast growth factors (fibroblast growth factor, FGF) pathway is considered to be related to tumor cell proliferation, metastasis and angiogenesis, more and more researches proved the amplification of fibroblast growth factor receptor (FGFR) in squamous cell lung cancer. Experiments in vivo and in vitro found that blocking FGF pathway could reduce the proliferation of tumor cells and inhibit metastasis. The FGF pathway might be a new target for treatment of squamous cell lung cancer. This article reviews the effect of FGFR in tumorigenesis,as well as the prospect as a therapeutic target in non-small cell lung cancer.
Fibroblast growth factor receptor 2: a therapeutic target in gastric cancer.
Hong Liu,Han Yu,Liu Jinqiang,Brain Lubi
Expert review of gastroenterology & hepatology
Gastric cancer remains a leading cause of cancer-related death in the world. FGF receptor 2 (FGFR2) is preferentially amplified and overexpressed in the diffuse type of gastric cancer. This review evaluates the expression and function of FGFR2 in gastric cancer, and analyzes the use of its inhibitors for gastric cancer therapy. This review also discusses the limitations of FGFR2-based therapy, and envisages future developments toward the clinical applications of FGFR2.
Is fibroblast growth factor receptor 4 a suitable target of cancer therapy?
Heinzle Christine,Erdem Zeynep,Paur Jakob,Grasl-Kraupp Bettina,Holzmann Klaus,Grusch Michael,Berger Walter,Marian Brigitte
Current pharmaceutical design
Fibroblast growth factors (FGF) and their tyrosine kinase receptors (FGFR) support cell proliferation, survival and migration during embryonic development, organogenesis and tissue maintenance and their deregulation is frequently observed in cancer development and progression. Consequently, increasing efforts are focusing on the development of strategies to target FGF/FGFR signaling for cancer therapy. Among the FGFRs the family member FGFR4 is least well understood and differs from FGFRs1-3 in several aspects. Importantly, FGFR4 deletion does not lead to an embryonic lethal phenotype suggesting the possibility that its inhibition in cancer therapy might not cause grave adverse effects. In addition, the FGFR4 kinase domain differs sufficiently from those of FGFRs1-3 to permit development of highly specific inhibitors. The oncogenic impact of FGFR4, however, is not undisputed, as the FGFR4-mediated hormonal effects of several FGF ligands may also constitute a tissue-protective tumor suppressor activity especially in the liver. Therefore it is the purpose of this review to summarize all relevant aspects of FGFR4 physiology and pathophysiology and discuss the options of targeting this receptor for cancer therapy.
Clinical significance of fibroblast growth factor receptor-3 mutations in bladder cancer: a systematic review and meta-analysis.
Liu X,Zhang W,Geng D,He J,Zhao Y,Yu L
Genetics and molecular research : GMR
Mutations in the fibroblast growth factor receptor-3 (FGFR3) gene are frequently found in bladder cancer, but their prognostic value remains controversial. To globally summarize the association between FGFR3 mutations and the grade and stage of bladder cancer, and to analyze the predictive role of FGFR3 mutations with respect to survival, eligible studies were identified and assessed for quality through multiple search strategies. Risk ratio (RR) data were collected from studies comparing the number of FGFR3 mutants among low-grade and early-stage bladder cancer patients to the number among high-grade and late-stage patients. Hazard ratio (HR) data were collected from studies comparing survival in patients with mutant FGFR3 genes to those with wild-type genes. Studies were pooled, and the RRs of grade and stage and the HRs of survival were calculated. Thirty studies were included in the present meta-analysis. FGFR3 mutations were found to be closely associated with low-grade and early-stage bladder cancer, showing pooled RRs = 2.948 [95% confidence interval (CI) = 2.357-3.688] and 2.845 (95%CI = 2.145- 3.773), respectively. Notably, patients with FGFR3 mutations tended to show better disease-, progress-, and recurrence-free survival (HR = 0.561, 95%CI = 0.405-0.779), and better disease-specific survival (HR = 0.363, 95%CI = 0.266-0.496). This study demonstrated that FGFR3 mutations are closely related to low grade, early stage, and better survival among bladder cancer patients.
Targeting fibroblast growth factor receptor in breast cancer: a promise or a pitfall?
Bedussi Francesca,Bottini Alberto,Memo Maurizio,Fox Stephen B,Sigala Sandra,Generali Daniele
Expert opinion on therapeutic targets
INTRODUCTION:Fibroblast growth factors (FGFs) along with their receptors (FGFRs) are involved in several cellular functions, from embryogenesis to metabolism. Because of the ability of FGFR signalling to induce cell proliferation, migration and survival in cancer, these have been found to become overactivated by several mechanisms, including gene amplification, chromosomal translocation and mutations. New evidences indicate that FGFs and FGFRs may act in an oncogenic fashion to promote multiple steps of cancer progression by inducing mitogenic and survival signals, as well as promoting epithelial-to-mesenchymal transition, invasion and tumour angiogenesis. This review focuses on the predictive and prognostic role of FGFRs, the role of FGFR signalling and how it may be most appropriately therapeutically targeted in breast cancer. AREAS COVERED:Activation of the FGFR pathway is a common event in many cancer types and for this reason FGFR is an important potential target in cancer treatment. Relevant literature was reviewed to identify current and future role of FGFR family as a possible guide for selecting those patients who would be poor or good responders to the available or the upcoming target therapies for breast cancer treatment. EXPERT OPINION:The success of a personalised medicine approach using targeted therapies ultimately depends on being capable of identifying the patients who will benefit the most from any given drug. Outlining the molecular mechanisms of FGFR signalling and discussing the role of this pathway in breast cancer, we would like to endorse the incorporation of specific patient selection biomakers with the rationale for therapeutic intervention with FGFR-targeted therapy in breast cancer.
The ins and outs of fibroblast growth factor receptor signalling.
Coleman Stacey J,Bruce Charo,Chioni Athina-Myrto,Kocher Hemant M,Grose Richard P
Clinical science (London, England : 1979)
FGFR (fibroblast growth factor receptor) signalling plays critical roles in embryogensis, adult physiology, tissue repair and many pathologies. Of particular interest over recent years, it has been implicated in a wide range of cancers, and concerted efforts are underway to target different aspects of FGFR signalling networks. A major focus has been identifying the canonical downstream signalling pathways in cancer cells, and these are now relatively well understood. In the present review, we focus on two distinct but emerging hot topics in FGF biology: its role in stromal cross-talk during cancer progression and the potential roles of FGFR signalling in the nucleus. These neglected areas are proving to be of great interest clinically and are intimately linked, at least in pancreatic cancer. The importance of the stroma in cancer is well accepted, both as a conduit/barrier for treatment and as a target in its own right. Nuclear receptors are less acknowledged as targets, largely due to historical scepticism as to their existence or importance. However, increasing evidence from across the receptor tyrosine kinase field is now strong enough to make the study of nuclear growth factor receptors a major area of interest.
Fibroblast growth factor receptor 1 as a target for the therapy of renal cell carcinoma.
Tsimafeyeu Ilya,Bratslavsky Gennady
Dysregulation of fibroblast growth factor (FGF) signaling in renal cell carcinoma is now well understood, and it is becoming increasingly likely that certain tumors become dependent on an activation of this pathway for their growth and survival. Dissecting the FGF/FGF receptor (FGFR) pathway offers the hope of developing new therapeutic approaches that selectively target the FGF/FGFR axis in patients whose tumors are known to harbor FGF/FGFR dysregulation. In this review, we summarize the existing data on the role of FGFR1 in the pathogenesis of renal cell carcinoma and discuss methodological issues for drug investigation in this setting.
The potential of fibroblast growth factor/fibroblast growth factor receptor signaling as a therapeutic target in tumor angiogenesis.
Ronca Roberto,Giacomini Arianna,Rusnati Marco,Presta Marco
Expert opinion on therapeutic targets
INTRODUCTION:Fibroblast growth factors (FGFs) are endowed with a potent pro-angiogenic activity. Activation of the FGF/FGF receptor (FGFR) system occurs in a variety of human tumors. This may lead to neovascularization, supporting tumor progression and metastatic dissemination. Thus, a compelling biologic rationale exists for the development of anti-FGF/FGFR agents for the inhibition of tumor angiogenesis in cancer therapy. AREAS COVERED:A comprehensive search on PubMed was performed to identify studies on the role of the FGF/FGFR system in angiogenesis. Endothelial FGFR signaling, the pro-angiogenic function of canonical FGFs, and their role in human tumors are described. In addition, experimental approaches aimed at the identification and characterization of nonselective and selective FGF/FGFR inhibitors and their evaluation in clinical trials are summarized. EXPERT OPINION:Different approaches can be envisaged to inhibit the FGF/FGFR system, a target for the development of 'two-compartment' anti-angiogenic/anti-tumor agents, including FGFR selective and nonselective small-molecule tyrosine kinase inhibitors, anti-FGFR antibodies, and FGF ligand traps. Further studies are required to define the correlation between tumor vascularization and activation of the FGF/FGFR system and for the identification of cancer patients more likely to benefit from anti-FGF/FGFR treatments. In addition, advantages and disadvantages about the use of selective versus non-selective FGF inhibitors remain to be elucidated.
Rationale for targeting fibroblast growth factor receptor signaling in breast cancer.
André Fabrice,Cortés Javier
Breast cancer research and treatment
Fibroblast growth factor receptor (FGFR) signaling is involved in multiple biological processes, including cell proliferation, survival, differentiation, migration, and apoptosis during embryonic development and adult tissue homeostasis. Given its role in the activation of critical signaling pathways, aberrant FGFR signaling has been implicated in multiple cancer types. A comprehensive search of PubMed and congress abstracts was conducted to identify reports on FGFR pathway components in breast cancer. In breast cancers, FGFR1 and FGFR4 gene amplification and single nucleotide polymorphisms in FGFR2 and FGFR4 have been detected. Commonly, these FGFR aberrations and gene amplifications lead to increased FGFR signaling and have been linked with poor prognosis and resistance to breast cancer treatments. Here, we review the role of FGFR signaling and the impact of FGFR genetic amplifications/aberrations on breast tumors. In addition, we summarize the most recent preclinical and clinical data on FGFR-targeted therapies in breast cancer. Finally, we highlight the ongoing clinical trials of the FGFR-targeted agents dovitinib, AZD4547, lucitanib, BGJ398, and JNJ-42756493, which are selected for patients with FGFR pathway-amplified breast cancer. Aberrant FGFR pathway amplification may drive some breast cancers. Inhibition of FGFR signaling is being explored in the clinic, and data from these trials may refine our ability to select patients who would best respond to these treatments.
Careless talk costs lives: fibroblast growth factor receptor signalling and the consequences of pathway malfunction.
Carter Edward P,Fearon Abbie E,Grose Richard P
Trends in cell biology
Since its discovery 40 years ago, fibroblast growth factor (FGF) receptor (FGFR) signalling has been found to regulate fundamental cellular behaviours in a wide range of cell types. FGFRs regulate development, homeostasis, and repair and are implicated in many disorders and diseases; and indeed, there is extensive potential for severe consequences, be they developmental, homeostatic, or oncogenic, should FGF-FGFR signalling go awry, so careful control of the pathway is critically important. In this review, we discuss the recent developments in the FGF field, highlighting how FGFR signalling works in normal cells, how it can go wrong, how frequently it is compromised, and how it is being targeted therapeutically.
Fibroblast growth factor receptor 2 fusions as a target for treating cholangiocarcinoma.
Borad Mitesh J,Gores Gregory J,Roberts Lewis R
Current opinion in gastroenterology
PURPOSE OF REVIEW:This review will cover the role of the fibroblast growth factor pathway in the pathogenesis, targeted therapy potential and prognostic value in patients with cholangiocarcinoma (CCA). RECENT FINDINGS:Recent studies that have identified fibroblast growth factor receptor 2 (FGFR2) fusions, prognostic implications of FGFR2 fusions, treatment strategies that target FGFR2 in CCA and future directions for understanding and targeting the FGFR2 pathway in this disease, will be discussed. SUMMARY:Understanding the role of the FGFR2 pathway as a disease pathogenetic mechanism and the ability to develop targeted therapies and diagnostics surrounding this concept are critical elements toward developing novel targeted approaches in CCA.
Role of the fibroblast growth factor receptor axis in cholangiocarcinoma.
Journal of gastroenterology and hepatology
Advanced cholangiocarcinoma (CCA) is a highly lethal disease with limited therapeutic options beyond cytotoxic chemotherapy. Molecular profiling of CCA has provided insights into the pathogenesis of this disease and identified potential therapeutic targets. The fibroblast growth factor receptor (FGFR) axis is important for maintaining tissue homeostasis. Aberrations in FGFR activity have been implicated in the development and progression of CCA and other malignancies, which has generated significant interest in exploring FGFR's therapeutic potential. FGFR2 fusion events are present in up to 17% of intrahepatic CCAs and appear to predict sensitivity to FGFR inhibitors even after progression on chemotherapy. These observations have led to a clinical trial evaluating FGFR inhibition in patients with CCA enriched for FGFR alterations. This review summarizes current knowledge about the role of the FGFR pathway in cholangiocarcinogenesis and ongoing work in developing FGFR-directed therapies as an antineoplastic strategy for CCA.
Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications.
Helsten Teresa,Schwaederle Maria,Kurzrock Razelle
Cancer metastasis reviews
Fibroblast growth factors (FGFs) and their receptors (FGFRs) are transmembrane growth factor receptors with wide tissue distribution. FGF/FGFR signaling is involved in neoplastic behavior and also development, differentiation, growth, and survival. FGFR germline mutations (activating) can cause skeletal disorders, primarily dwarfism (generally mutations in FGFR3), and craniofacial malformation syndromes (usually mutations in FGFR1 and FGFR2); intriguingly, some of these activating FGFR mutations are also seen in human cancers. FGF/FGFR aberrations reported in cancers are mainly thought to be gain-of-function changes, and several cancers have high frequencies of FGFR alterations, including breast, bladder, or squamous cell carcinomas (lung and head and neck). FGF ligand aberrations (predominantly gene amplifications) are also frequently seen in cancers, in contrast to hereditary syndromes. There are several pharmacologic agents that have been or are being developed for inhibition of FGFR/FGF signaling. These include both highly selective inhibitors as well as multi-kinase inhibitors. Of note, only four agents (ponatinib, pazopanib, regorafenib, and recently lenvatinib) are FDA-approved for use in cancer, although the approval was not based on their activity against FGFR. Perturbations in the FGFR/FGF signaling are present in both inherited and malignant diseases. The development of potent inhibitors targeting FGF/FGFR may provide new tools against disorders caused by FGF/FGFR alterations.
Targeting fibroblast growth factor receptor pathway in breast cancer.
Criscitiello Carmen,Esposito Angela,De Placido Sabino,Curigliano Giuseppe
Current opinion in oncology
PURPOSE OF REVIEW:The purpose of this manuscript is to critically review the literature published last year focusing on the rationale and potential role of fibroblast growth factor receptor (FGFR) inhibitors in breast cancer. RECENT FINDINGS:Substantial evidence indicates that aberrant FGFR signaling is involved in the pathogenesis of breast cancer. FGFR targeting has progressed in the last years due to the development of novel agents inhibiting FGF or FGFR. One of the most investigated FGFR inhibitors is lucitanib, which has shown clinical activity in breast cancer, especially in presence of FGF aberrations. Moving forward, the design and development of FGFR4 inhibitors and covalent FGFR inhibitors may overcome resistance to first-generation FGFR inhibitors. SUMMARY:Inhibition of FGFR signaling is under investigation in the treatment of breast cancer with increasing interest. Next steps will include the optimal selection of patients to be treated with this class of drugs and the development of new-generation FGFR inhibitors to face with the resistance issue.
The role of mutations and overexpression of the fibroblast growth factor receptor-3 in bladder cancer.
Wang Q Y,Zhao Y,Zhang R
Bladder cancer (BC) is the seventh most common cancer worldwide. Throughout the last decade, several studies demonstrated that the fibroblast growth factor (FGF) signalling is altered in a significant proportion of patients with BC. FGF receptor (FGFR) 3 may thus serve as a promising biomarker for BC. Mutations of this gene are prevalent in BC (e.g., found in 74% of non-invasive papillary tumours), suggesting that FGFR3 status is an important event in BC. The aim of this review was to overview the outcomes of different mutations in FGFR3 receptor in the context of BC. We first described FGFR3 receptor and continue with mutations of FGFR3 gene, including activating mutations and overexpression of this gene. Finally, we addressed the clinical relevance of mutated FGFR3 gene.
Fibroblast Growth Factor (FGF) Receptor/FGF Inhibitors: Novel Targets and Strategies for Optimization of Response of Solid Tumors.
Hierro Cinta,Rodon Jordi,Tabernero Josep
Seminars in oncology
The fibroblast growth factor receptor (FGFR) pathway plays a major role in several biological processes, from organogenesis to metabolism homeostasis and angiogenesis. Several aberrations, including gene amplifications, point mutations, and chromosomal translocations have been described across solid tumors. Most of these molecular alterations promote multiple steps of carcinogenesis in FGFR oncogene-addicted cells, increasing cell proliferation, angiogenesis, and drug resistance. Data suggest that upregulation of FGFR signaling is a common event in many cancer types. The FGFR pathway thus arises as a potential promising target for cancer treatment. Several FGFR inhibitors are currently under development. Initial preclinical results have translated into limited successful clinical responses when first-generation, nonspecific FGFR inhibitors were evaluated in patients. The future development of selective and unselective FGFR inhibitors will rely on a better understanding of the tissue-specific role of FGFR signaling and identification of biomarkers to select those patients who will benefit the most from these drugs. Further studies are warranted to establish the predictive significance of the different FGFR-aberrations and to incorporate them into clinical algorithms, now that second-generation, selective FGFR inhibitors exist.
Fibroblast Growth Factor Receptor (FGFR): A New Target for Non-small Cell Lung Cancer Therapy.
Biello Federica,Burrafato Giovanni,Rijavec Erika,Genova Carlo,Barletta Giulia,Truini Anna,Coco Simona,Bello Maria Giovanna Dal,Alama Angela,Boccardo Francesco,Grossi Francesco
Anti-cancer agents in medicinal chemistry
Lung cancer is still the leading cause of cancer related death worldwide. Fibroblast growth factor receptor (FGFR) is a tirosine-kinase receptor that is seen to be amplified or mutated in non-small cell lung cancer (NSCLC) and it plays a crucial role in tumour development and maintenance. The authors analyzed the state of the art of FGFR by reviewing the current literature. Fibroblast growth factor (FGF)-FGFR pathway and their aberrations are described, with the evaluation of their possible prognostic role in NSCLC and in particular in squamous cell carcinomas, in which FGFR is more often amplified. New therapeutic agents targeting FGFR signaling have been developed and are now in clinical evaluation. Dysregulation of FGF signaling in tumour cells is related to FGFR gene amplification or mutation, although it is still uncertain which of these aberrations represents a real predictor of response to specific inhibitors. However, recent evidence has questioned whether FGFR is a real target in squamous cell histology. The effectiveness of FGFR inhibitors is also still unclear since there are no clinical data on selected patients. Moreover, the management of specific side effects related to inhibition of the physiological role of FGF should be more thorough.
Fibroblast Growth Factor Receptor Family Members as Prognostic Biomarkers in Head and Neck Squamous Cell Carcinoma: A Systematic Review.
Ipenburg Norbertus A,Koole Koos,Liem K Seng,van Kempen Pauline M W,Koole Ron,van Diest Paul J,van Es Robert J J,Willems Stefan M
BACKGROUND:Since head and neck cancer is characterized by poor survival rates, there is a demand for novel therapeutic targets and prognostic biomarkers. An upcoming therapeutic target is the fibroblast growth factor receptor (FGFR) family. However, their prognostic role in head and neck cancer remains unclear. OBJECTIVE:To systematically review current evidence on the prognostic value of FGFR family members in head and neck squamous cell carcinoma (HNSCC). METHODS:A systematic search of PubMed, Embase, and the Cochrane Library was performed for publications up to 14 May 2014. Two reviewers screened all articles and included prognostic studies on the molecular biomarkers FGFR1-5 in any type of HNSCC. Relevant studies were assessed on risk of bias using the Quality in Prognostic Studies (QUIPS) tool. Data on FGFR aberrations and survival outcome were extracted from relevant studies. The prognostic value of FGFR aberrations was compared among studies. RESULTS:The initial search yielded 1568 publications of which 12 fulfilled the inclusion criteria. Four studies reported FGFR1 gene amplification (9.3-17.4 %) and FGFR1 protein overexpression (11.8 %) in HNSCC. FGFR1 protein expression by cancer-associated fibroblasts correlated with poor survival outcome in one study (p < 0.01). Eight studies reported high rates of FGFR4 Gly388Arg polymorphisms (32.5-54.2 %) and FGFR4 protein overexpression (16-35 %), with varying correlations with survival. So far, no studies assessed the prognostic role of FGFR2, FGFR3, or FGFR5 in HNSCC. LIMITATIONS:Significant risk of bias has been identified among included studies. Therefore, cautious interpretation of the results is recommended. CONCLUSION:In conclusion, evidence was found for prognostic value of FGFR1 expression in cancer-associated fibroblasts in HNSCC. Prognostic evidence on the other FGFR family members in HNSCC is limited and conflicting. This emphasizes the need for future well-conducted prognostic studies.
Fibroblast growth factor receptor signaling as therapeutic targets in gastric cancer.
Yashiro Masakazu,Matsuoka Tasuku
World journal of gastroenterology
Fibroblast growth factor receptors (FGFRs) regulate a variety of cellular functions, from embryogenesis to adult tissue homeostasis. FGFR signaling also plays significant roles in the proliferation, invasion, and survival of several types of tumor cells. FGFR-induced alterations, including gene amplification, chromosomal translocation, and mutations, have been shown to be associated with the tumor initiation and progression of gastric cancer, especially in diffuse-type cancers. Therefore, the FGFR signaling pathway might be one of the therapeutic targets in gastric cancer. This review aims to provide an overview of the role of FGFR signaling in tumorigenesis, tumor progression, proliferation, and chemoresistance. We also discuss the accumulating evidence that demonstrates the effectiveness of using clinical therapeutic agents to inhibit FGFR signaling for the treatment of gastric cancer.
Association between fibroblast growth factor receptor-2 gene polymorphism and risk of breast cancer in Chinese populations: A HuGE review and meta-analysis.
Yang Yong-Bin,Zhao Zhan-Xue,Huang Wei,Liu Hui,Tan Yan-Li,Wang Wei-Ming
Journal of cancer research and therapeutics
AIM OF STUDY:To evaluate the effect of fibroblast growth factor receptor.2. (FGFR2) on genetic susceptibility for breast cancer. (BC) in Chinese populations. MATERIALS AND METHODS:A computerized literature search was carried out in PubMed, Chinese Biomedical Database. (CBM), and Chinese National Knowledge Infrastructure. (CNKI) to collect relevant articles. Pooled odds ratio. (OR) and 95% confidence interval. (CI) were used to assess the strength of the associations. RESULTS:A total of 21 articles involving a total of 15 polymorphisms of the FGFR2 gene were included in the meta-analysis. Due to the limited studies for rs17102287, rs2981578, rs3135718, rs3803662, rs3750817, rsl0510097, rsl7542768, rs13387042, and rs1982073; we only pooled the six polymorphisms. (rs11200014, rs1219648, rs2420946, rs2912778, rs2981579, and rs2981582) into this meta. ANALYSIS:Overall, significantly increased BC risk was associated with five polymorphisms. (rs2981579, rs2981582, rs1219648, rs2420946, and rs2912778) when all studies were pooled into the meta. ANALYSIS:When stratified by ethnicity and source of controls, similar results were also detected. However, for rs2981579 no significant association was found among Chinese Han in all genetic models. CONCLUSION:Our meta-analysis suggests that FGFR2 is likely an important genetic marker contributing to susceptibility of BC. We recommend that these single nucleotide polymorphisms to be included in future association studies and functional assays.
Targeting the fibroblast growth factor receptor family in cancer.
Hallinan Niamh,Finn Stephen,Cuffe Sinead,Rafee Shereen,O'Byrne Kenneth,Gately Kathy
Cancer treatment reviews
Fibroblast growth factors (FGFs) regulate a plethora of biological functions, in both the embryonic and adult stages of development, binding their cognate receptors and thus activating a variety of downstream signalling pathways. Deregulation of the FGF/FGFR signalling axis, observed in multifarious tumor types including squamous non-small cell lung cancer, occurs through genomic FGFR alterations that drive ligand-independent receptor signalling or alterations that support ligand-dependent activation. Mutations are not restricted to the tyrosine kinase domain and aberrations appear to be tumor type dependent. As well as its complementarity and synergy with VEGF of particular interest is the interplay between FGFR and EGFR and the ability of these pathways to offer a compensatory signalling escape mechanism when either is inhibited. Hence there exists a rationale for a combinatorial approach to inhibition of these dysregulated pathways to reverse drug resistance. To date, several multi-target tyrosine kinase inhibitors as well as FGFR specific tyrosine kinase inhibitors (TKIs), monoclonal antibodies and FGF ligand traps have been developed. Promising preclinical data has resulted in several drugs entering clinical trials. This review explores aberrant FGFR and its potential as a therapeutic target in solid tumors.
Fibroblast growth factor receptor signaling in kidney and lower urinary tract development.
Walker Kenneth A,Sims-Lucas Sunder,Bates Carlton M
Pediatric nephrology (Berlin, Germany)
Fibroblast growth factor receptors (FGFRs) and FGF ligands are highly expressed in the developing kidney and lower urinary tract. Several classic studies showed many effects of exogenous FGF ligands on embryonic renal tissues in vitro and in vivo. Another older landmark publication showed that mice with a dominant negative Fgfr fragment had severe renal dysplasia. Together, these studies revealed the importance of FGFR signaling in kidney and lower urinary tract development. With the advent of modern gene targeting techniques, including conditional knockout approaches, several publications have revealed critical roles for FGFR signaling in many lineages of the kidney and lower urinary tract at different stages of development. FGFR signaling has been shown to be critical for early metanephric mesenchymal patterning, Wolffian duct patterning including induction of the ureteric bud, ureteric bud branching morphogenesis, nephron progenitor survival and nephrogenesis, and bladder mesenchyme patterning. FGFRs pattern these tissues by interacting with many other growth factor signaling pathways. Moreover, the many genetic Fgfr and Fgf animal models have structural defects mimicking numerous congenital anomalies of the kidney and urinary tract seen in humans. Finally, many studies have shown how FGFR signaling is critical for kidney and lower urinary tract patterning in humans.
Fibroblast Growth Factor Receptor 1 Gene Amplification in Nonsmall Cell Lung Cancer.
Miao Jian-Long,Liu Rui-Juan,Zhou Jin-Hua,Meng Shu-Hua
Chinese medical journal
OBJECTIVE:To review the prevalence and prognostic significance of fibroblast growth factor receptor 1 (FGFR1) amplification and to establish an association between FGFR1 amplification and the clinical characteristics of nonsmall cell lung cancer (NSCLC). DATA SOURCES:We searched PubMed for English-language studies published between January 2010 and May 2016. STUDY SELECTION:We included all relevant articles, with no limitation of study design. RESULTS:FGFR1 amplification was reported in 8.7-20.0% of NSCLC cases and was significantly more frequent in squamous cell carcinomas (SCCs) (9.7-28.3%) than in adenocarcinomas (ADCs) (0-15.0%). The rates of FGFR1 amplification were as follows: males, 13.9-22.1%; females, 0-20.1%; Stage I NSCLC, 9.3-24.1%; Stage II NSCLC, 12.9-25.0%; Stage III NSCLC, 8.2-19.5%; Stage IV NSCLC, 0-12.5%; current smokers, 13.3-29.0%; former smokers, 2.5-23.0%; and nonsmokers, 0-22.2%. Overall survival was 43.9-70.8 months in patients with FGFR1 amplification and 42.4-115.0 months in patients with no FGFR1 amplification; disease-free survival was 22.5-58.5 months and 52.4-94.6 months, respectively. CONCLUSIONS:FGFR1 amplification is more frequent in SCCs than in ADCs. The association between FGFR1 amplification and clinical characteristics (gender, smoking status, and disease stage) and the prognostic significance of FGFR1 amplification in NSCLC remain controversial.
Tumor Necrosis Factor Receptor Mediates Fibroblast Growth Factor-Inducible 14 Signaling.
Wang Xuening,Xiao Shengxiang,Xia Yumin
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
Tumor necrosis factor (TNF)-related weak inducer of apoptosis (TWEAK) engages its sole receptor, fibroblast growth factor-inducible 14 (Fn14), which participates in various inflammatory and immunologic processes. TWEAK/Fn14 interaction induces different cell fates depending on the local microenvironment, which correlates with certain expression profiles of TNF receptors (TNFR). The predominant expression of TNFR1 or TNFR2 facilitates cell death or proliferation, respectively, on TWEAK/Fn14 activation. TNFR-associated factors (TRAF) interact with Fn14, cellular inhibitor of apoptosis protein (cIAP)-1, and TNFR, consequently transducing signals from TWEAK to downstream cytokines and cell cycle mediators. An Fn14-TRAF2-TNFR axis has been suggested in the function of TWEAK/Fn14 signaling, which may serve as a target in the development of novel therapeutic strategies for many diseases that have Fn14-overexpressing cells in affected tissues. The aims of this review are: 1) to present the main results on TWEAK/Fn14 regulation of cell fates, 2) to analyze the mechanism of the Fn14-TRAF2-TNFR axis, and 3) to summarize the potential strategies in the pharmacologic targeting of this axis.
Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application.
Chae Young Kwang,Ranganath Keerthi,Hammerman Peter S,Vaklavas Christos,Mohindra Nisha,Kalyan Aparna,Matsangou Maria,Costa Ricardo,Carneiro Benedito,Villaflor Victoria M,Cristofanilli Massimo,Giles Francis J
The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) is a tyrosine kinase signaling pathway that has a fundamental role in many biologic processes including embryonic development, tissue regeneration, and angiogenesis. Increasing evidence indicates that this pathway plays a critical role in oncogenesis via gene amplification, activating mutations, or translocation in tumors of various histologies. With multiplex sequencing technology, the detection of FGFR aberrations has become more common and is tied to cancer cell proliferation, resistance to anticancer therapies, and neoangiogenesis. Inhibition of FGFR signaling appears promising in preclinical studies, suggesting a pathway of clinical interest in the development of targeted therapy. Phase I trials have demonstrated a manageable toxicity profile. Currently, there are multiple FGFR inhibitors under study with many non-selective (multi-kinase) inhibitors demonstrating limited clinical responses. As we progress from the first generation of non-selective drugs to the second generation of selective FGFR inhibitors, it is clear that FGFR aberrations do not behave uniformly across cancer types; thus, a deeper understanding of biomarker strategies is undoubtedly warranted. This review aims to consolidate data from recent clinical trials with a focus on selective FGFR inhibitors. As Phase II clinical trials emerge, concentration on patient selection as it pertains to predicting response to therapy, feasible methods for overcoming toxicity, and the likelihood of combination therapies should be utilized. We will also discuss qualities that may be desirable in future generations of FGFR inhibitors, with the hope that overcoming these current barriers will expedite the availability of this novel class of medications.
Investigational drugs targeting fibroblast growth factor receptor in the treatment of non-small cell lung cancer.
Rijavec Erika,Genova Carlo,Barletta Giulia,Biello Federica,Rossi Giovanni,Tagliamento Marco,Dal Bello Maria Giovanna,Coco Simona,Vanni Irene,Boccardo Simona,Alama Angela,Grossi Francesco
Expert opinion on investigational drugs
INTRODUCTION:Fibroblast growth factor receptor (FGFR) due to its central role in regulating cell survival, is a promising target for cancer therapeutics. Dysregulation of the FGFR pathway has been observed in several malignancies, including non-small cell lung cancer (NSCLC) particularly in patients with squamous histology. Areas covered: The aim of this article is to review the most relevant findings of clinical trials investigating drugs targeting FGFR pathway: such as FGFR tyrosine kinase inhibitors (TKIs), FGFR monoclonal antibodies and FGF ligand traps in NSCLC patients. Expert opinion: At present, clinical activity of drugs targeting FGFR in NSCLC is disappointing. Further studies are needed in order to better identify patients who might benefit from these drugs and to clarify the mechanisms of resistance to these compounds.
Genetics of Pheochromocytomas and Paragangliomas: An Overview on the Recently Implicated Genes MERTK, MET, Fibroblast Growth Factor Receptor 1, and H3F3A.
Toledo Rodrigo Almeida
Endocrinology and metabolism clinics of North America
Genomic studies conducted by different centers have uncovered various new genes mutated in pheochromocytomas and paragangliomas (PPGLs) at germline, mosaic, and/or somatic levels, greatly expanding our knowledge of the genetic events occurring in these tumors. The current review focuses on very new findings and discusses the previously not recognized role of MERTK, MET, fibroblast growth factor receptor 1, and H3F3A genes in syndromic and nonsyndromic PPGLs. These 4 new genes were selected because although their association with PPGLs is very recent, mounting evidence was generated that rapidly consolidated the prominence of these genes in the molecular pathogenesis of PPGLs.
Prognostic role of fibroblast growth factor receptor 2 in human solid tumors: A systematic review and meta-analysis.
Liu Gang,Xiong Disheng,Xiao Rui,Huang Zhengjie
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine
In the past decades, the oncogenic role of fibroblast growth factor receptor 2 has been demonstrated in a number of cancer types. However, studies have reported contradictory findings concerning the correlation between fibroblast growth factor receptor 2 expression and prognosis in solid tumors. To address this discrepancy, we performed a meta-analysis with 18 published studies (2975 patients) retrieved from PubMed, EMBASE, and Web of science. Data were extracted and computed into odds ratios. The results showed that fibroblast growth factor receptor 2 overexpression was significantly associated with decreased 3-year overall survival (odds ratio = 1.93, 95% confidence interval: 1.30-2.85, p = 0.001) and 5-year overall survival (odds ratio = 1.62, 95% confidence interval: 1.07-2.44, p = 0.02) in patients with solid tumors. Subgroup analysis revealed that high fibroblast growth factor receptor 2 expression was also associated with poor prognosis of gastric cancer, hepatocellular carcinoma, and esophageal cancer, but not correlated with pancreatic cancer. In conclusion, fibroblast growth factor receptor 2 overexpression is correlated with decreased survival in most solid tumors, suggesting that the expression status of fibroblast growth factor receptor 2 is a valuable prognostic biomarker and a novel therapeutic target in human solid tumors.
Targeting the fibroblast growth factor receptor 2 in gastric cancer: promise or pitfall?
Hierro C,Alsina M,Sánchez M,Serra V,Rodon J,Tabernero J
Annals of oncology : official journal of the European Society for Medical Oncology
Gastric cancer is the third leading cause of death from cancer worldwide. Systemic chemotherapy remains the mainstay therapeutic option for this poor prognosis cancer. Trastuzumab, the epidermal growth factor receptor 2 (ERBB2 or HER2)-antibody, is the only biological agent approved for the molecularly selected population of HER2-positive gastric cancer patients. Over the last decade, several groups have been working for deepening into the molecular characterization of gastric cancer, shedding some light into the heterogeneity of this tumour. The published data have broadened the landscape towards a future molecular classification into several subtypes of gastric cancer, enabling a better selection of the optimal therapeutic strategy. The fibroblast growth factor receptor (FGFR) pathway plays a key role in gastric cancer pathogenesis, with 1.2%-9% of gastric cancer patients harbouring FGFR2 amplifications. Several selective FGFR inhibitors have been developed in the last years, with promising efficacy signals. However, there is still scarce evidence of the most reliant molecular determinants of response to these targeted agents. Homogeneous high-level clonal FGFR2-amplification, high FGFR2 mRNA or protein levels, specific FGFR2 C3 isoform expression, FGF ligand co-overexpression or detection of FGFR2 copy number in plasma circulating tumour DNA, are considered some of the potential predictive biomarkers to the FGFR inhibition. The successful development of highly specific FGFR inhibitors will rely on our capacity of establishing new personalized strategies, based on a deeper knowledge of the key alterations that drive oncogenesis in gastric cancer. Further efforts seem mandatory in order to implement accurate predictive biomarkers in the next stages of the FGFR inhibitors development.
Fibroblast Growth Factor Receptor 2 Signaling in Breast Cancer.
Lei Haipeng,Deng Chu-Xia
International journal of biological sciences
Fibroblast growth factor receptor 2 (FGFR2) is a membrane-spanning tyrosine kinase that mediates signaling for FGFs. Recent studies detected various point mutations of FGFR2 in multiple types of cancers, including breast cancer, lung cancer, gastric cancer, uterine cancer and ovarian cancer, yet the casual relationship between these mutations and tumorigenesis is unclear. Here we will discuss possible interactions between FGFR2 signaling and several major pathways through which the aberrantly activated FGFR2 signaling may result in breast cancer development. We will also discuss some recent developments in the discovery and application of therapies and strategies for breast cancers by inhibiting FGFR2 activities.
Imaging of Skeletal Disorders Caused by Fibroblast Growth Factor Receptor Gene Mutations.
Sargar Kiran M,Singh Achint K,Kao Simon C
Radiographics : a review publication of the Radiological Society of North America, Inc
Fibroblast growth factors and fibroblast growth factor receptors (FGFRs) play important roles in human axial and craniofacial skeletal development. FGFR1, FGFR2, and FGFR3 are crucial for both chondrogenesis and osteogenesis. Mutations in the genes encoding FGFRs, types 1-3, are responsible for various skeletal dysplasias and craniosynostosis syndromes. Many of these disorders are relatively common in the pediatric population, and diagnosis is often challenging. These skeletal disorders can be classified based on which FGFR is affected. Skeletal disorders caused by type 1 mutations include Pfeiffer syndrome (PS) and osteoglophonic dysplasia, and disorders caused by type 2 mutations include Crouzon syndrome (CS), Apert syndrome (AS), and PS. Disorders caused by type 3 mutations include achondroplasia, hypochondroplasia, thanatophoric dysplasia (TD), severe achondroplasia with developmental delay and acanthosis nigricans, Crouzonodermoskeletal syndrome, and Muenke syndrome. Most of these mutations are inherited in an autosomal dominant fashion and are gain-of-function-type mutations. Imaging plays a key role in the evaluation of these skeletal disorders. Knowledge of the characteristic imaging and clinical findings can help confirm the correct diagnosis and guide the appropriate molecular genetic tests. Some characteristics and clinical findings include premature fusion of cranial sutures and deviated broad thumbs and toes in PS; premature fusion of cranial sutures and syndactyly of the hands and feet in AS; craniosynostosis, ocular proptosis, and absence of hand and foot abnormalities in CS; rhizomelic limb shortening, caudal narrowing of the lumbar interpediculate distance, small and square iliac wings, and trident hands in achondroplasia; and micromelia, bowing of the femora, and platyspondyly in TD. RSNA, 2017.
Fibroblast Growth Factor Receptor 2 () Mutation Related Syndromic Craniosynostosis.
Azoury Saïd C,Reddy Sashank,Shukla Vivek,Deng Chu-Xia
International journal of biological sciences
Craniosynostosis results from the premature fusion of cranial sutures, with an incidence of 1 in 2,100-2,500 live births. The majority of cases are non-syndromic and involve single suture fusion, whereas syndromic cases often involve complex multiple suture fusion. The fibroblast growth factor receptor 2 () gene is perhaps the most extensively studied gene that is mutated in various craniosynostotic syndromes including Crouzon, Apert, Pfeiffer, Antley-Bixler, Beare-Stevenson cutis gyrata, Jackson-Weiss, Bent Bone Dysplasia, and Seathre-Chotzen-like syndromes. The majority of these mutations are missense mutations that result in constitutive activation of the receptor and downstream molecular pathways. Treatment involves a multidisciplinary approach with ultimate surgical fixation of the cranial deformity to prevent further sequelae. Understanding the molecular mechanisms has allowed for the investigation of different therapeutic agents that can potentially be used to prevent the disorders. Further research efforts are need to better understand screening and effective methods of early intervention and prevention. Herein, the authors provide a comprehensive update on related syndromic craniosynostosis.
Role of fibroblast growth factor receptor-2 splicing in normal and cancer cells.
Frontiers in bioscience (Landmark edition)
Types 1-4 of fibroblast growth factor receptors (FGFR) are all expressed in various cancers. Because of its prominent role in carcinogenesis and cancer progression, FGFR-2, is being considered as a novel target in cancer treatment. Owing to the alternative splicing of its extracellular domain, FGFR-2 exists in two variants: IIIb and IIIc. FGFR-2 IIIb is mainly expressed in normal epithelial cells, as well as in oral mucosal, esophageal, gastric, colorectal, pancreatic, pulmonary, breast, endometrial, cervical, and prostate cancers. The IIIc variant of FGFR is expressed in mesenchymal cells, and during epithelial-mesenchymal transition (EMT), is expressed in colorectal, pancreatic, bladder, cervical, and prostate cancers. The FGFR IIIb and IIIc variants bind different forms of FGFs and exert autocrine and/or paracrine effects in cancers. Recent reports indicate that switching from IIIb to IIIc variants correlates with the aggressiveness of the cancers via EMT. Here, we discuss the expression, role, and regulatory mechanisms of IIIb and IIIc variants of FGFR in cancers.
Current Status of Fibroblast Growth Factor Receptor-Targeted Therapies in Breast Cancer.
Sobhani Navid,Ianza Anna,D'Angelo Alberto,Roviello Giandomenico,Giudici Fabiola,Bortul Marina,Zanconati Fabrizio,Bottin Cristina,Generali Daniele
Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, metastatic breast cancer has a poor prognosis. In an era of personalized medicine, there is an urgent need for better knowledge of the biology leading to the disease, which can lead to the design of increasingly accurate drugs against patients' specific molecular aberrations. Among one of the actionable targets is the fibroblast growth factor receptor (FGFR) pathway, triggered by specific ligands. The Fibroblast Growth Factor Receptors/Fibroblast Growth Factors (FGFRs/FGFs) axis offers interesting molecular targets to be pursued in clinical development. This mini-review will focus on the current knowledge of FGFR mutations, which lead to tumor formation and summarizes the state-of-the-art therapeutic strategies for targeted treatments against the FGFRs/FGFs axis in the context of BC.
Clinical outcomes of myeloid/lymphoid neoplasms with fibroblast growth factor receptor-1 (FGFR1) rearrangement.
Umino Kento,Fujiwara Shin-Ichiro,Ikeda Takashi,Toda Yumiko,Ito Shoko,Mashima Kiyomi,Minakata Daisuke,Nakano Hirofumi,Yamasaki Ryoko,Kawasaki Yasufumi,Sugimoto Miyuki,Yamamoto Chihiro,Ashizawa Masahiro,Hatano Kaoru,Sato Kazuya,Oh Iekuni,Ohmine Ken,Muroi Kazuo,Kanda Yoshinobu
Hematology (Amsterdam, Netherlands)
OBJECTIVE:Myeloid/lymphoid neoplasms with fibroblast growth factor receptor-1 (FGFR1) rearrangement are hematopoietic stem cell disorders with a poor prognosis, but no established standard therapy. METHODS:We experienced a patient with T-lymphoblastic lymphoma (LBL) associated with FGFR1 rearrangement who underwent cord blood transplantation, but died of pulmonary complication. We collected the clinical data of patients with FGFR1 rearrangement from the medical literature and analyzed 45 patients, including our patient. RESULTS:The primary diagnoses were myeloproliferative neoplasm (MPN) or myelodysplastic syndromes (MDS) in 14 and acute leukemia or LBL in 31. In MPN and MDS patients, the cumulative incidence of transformation to blast phase (BP) at 12 months was 46.2%. The 1-year overall survival (OS) from diagnosis in all cases was 43.1%. With regard to the impact of treatment response on survival, the achievement of complete response with a landmark at 2 months after diagnosis of BP was associated with a superior OS (40.0% vs. 26.0% P = 0.011 for 1-year OS from BP). Allogeneic hematopoietic stem cell transplantation (HSCT) was performed in 13 patients, and the 1-year OS from allogeneic HSCT was 61.5%. The hazard ratio for mortality was 0.34 (95% CI, 0.08-1.51, P = 0.15) for allogeneic HSCT treated as a time-dependent covariate, which suggests that allogeneic HSCT may confer a clinical benefit. CONCLUSION:The further accumulation of clinical data is needed to determine the optimal therapeutic approach for these neoplasms.
Role of fibroblast growth factor receptor 4 in cancer.
Tang Shuya,Hao Yilong,Yuan Yao,Liu Rui,Chen Qianming
Fibroblast growth factor receptors (FGFR) play a significant role in both embryonic development and in adults. Upon binding with ligands, FGFR signaling is activated and triggers various downstream signal cascades that are implicated in diverse biological processes. Aberrant regulations of FGFR signaling are detected in numerous cancers. Although FGFR4 was discovered later than other FGFR, information on the involvement of FGFR4 in cancers has significantly increased in recent years. In this review, the recent findings in FGFR4 structure, signaling transduction, physiological function, aberrant regulations, and effects in cancers as well as its potential applications as an anticancer therapeutic target are summarized.
Structure, activation and dysregulation of fibroblast growth factor receptor kinases: perspectives for clinical targeting.
Farrell Brendan,Breeze Alexander L
Biochemical Society transactions
The receptor tyrosine kinase family of fibroblast growth factor receptors (FGFRs) play crucial roles in embryonic development, metabolism, tissue homeostasis and wound repair via stimulation of intracellular signalling cascades. As a consequence of FGFRs' influence on cell growth, proliferation and differentiation, FGFR signalling is frequently dysregulated in a host of human cancers, variously by means of overexpression, somatic point mutations and gene fusion events. Dysregulation of FGFRs is also the underlying cause of many developmental dysplasias such as hypochondroplasia and achondroplasia. Accordingly, FGFRs are attractive pharmaceutical targets, and multiple clinical trials are in progress for the treatment of various FGFR aberrations. To effectively target dysregulated receptors, a structural and mechanistic understanding of FGFR activation and regulation is required. Here, we review some of the key research findings from the last couple of decades and summarise the strategies being explored for therapeutic intervention.
Fibroblast Growth Factor Receptor 4 Targeting in Cancer: New Insights into Mechanisms and Therapeutic Strategies.
Lang Liwei,Teng Yong
Fibroblast growth factor receptor 4 (FGFR4), a tyrosine kinase receptor for FGFs, is involved in diverse cellular processes, including the regulation of cell proliferation, differentiation, migration, metabolism, and bile acid biosynthesis. High activation of FGFR4 is strongly associated with the amplification of its specific ligand FGF19 in many types of solid tumors and hematologic malignancies, where it acts as an oncogene driving the cancer development and progression. Currently, the development and therapeutic evaluation of FGFR4-specific inhibitors, such as BLU9931 and H3B-6527, in animal models and cancer patients, are paving the way to suppress hyperactive FGFR4 signaling in cancer. This comprehensive review not only covers the recent discoveries in understanding FGFR4 regulation and function in cancer, but also reveals the therapeutic implications and applications regarding emerging anti-FGFR4 agents. Our aim is to pinpoint the potential of FGFR4 as a therapeutic target and identify new avenues for advancing future research in the field.
Fibroblast Growth Factor Receptor 4 (FGFR4) Selective Inhibitors as Hepatocellular Carcinoma Therapy: Advances and Prospects.
Lu Xiaoyun,Chen Hao,Patterson Adam V,Smaill Jeff B,Ding Ke
Journal of medicinal chemistry
Hepatocellular carcinoma (HCC) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Aberrant fibroblast growth factor 19 (FGF19) signaling through fibroblast growth factor receptor 4 (FGFR4) has been identified as an oncogenic driver for a subset of patients with HCC. FGFR4 is therefore a promising target for the treatment of HCC harboring aberrant FGF19-FGFR4 signaling, and several FGFR4 inhibitors have advanced to clinical trial. In this review, we summarize the latest developments in FGFR4 inhibitors, including the known pharmacophores, their binding mode, selectivity, and clinical implications, as well as the optimization strategy of introducing an acrylamide into a known pan-FGFR inhibitor targeting Cys552 of FGFR4 to provide selective covalent FGFR4 inhibitors.
Nuclear Fibroblast Growth Factor Receptor Signaling in Skeletal Development and Disease.
Tuzon Creighton T,Rigueur Diana,Merrill Amy E
Current osteoporosis reports
PURPOSE OF REVIEW:Fibroblast growth factor receptor (FGFR) signaling regulates proliferation and differentiation during development and homeostasis. While membrane-bound FGFRs play a central role in these processes, the function of nuclear FGFRs is also critical. Here, we highlight mechanisms for nuclear FGFR translocation and the effects of nuclear FGFRs on skeletal development and disease. RECENT FINDINGS:Full-length FGFRs, internalized by endocytosis, enter the nucleus through β-importin-dependent mechanisms that recognize the nuclear localization signal within FGFs. Alternatively, soluble FGFR intracellular fragments undergo nuclear translocation following their proteolytic release from the membrane. FGFRs enter the nucleus during the cellular transition between proliferation and differentiation. Once nuclear, FGFRs interact with chromatin remodelers to alter the epigenetic state and transcription of their target genes. Dysregulation of nuclear FGFR is linked to the etiology of congenital skeletal disorders and neoplastic transformation. Revealing the activities of nuclear FGFR will advance our understanding of 20 congenital skeletal disorders caused by FGFR mutations, as well as FGFR-related cancers.
Fibroblast Growth Factor Receptor Signaling in Skin Cancers.
Fibroblast growth factor (FGF)/Fibroblast growth factor receptor (FGFR) signaling regulates various cellular processes during the embryonic development and in the adult organism. In the skin, fibroblasts and keratinocytes control proliferation and survival of melanocytes in a paracrine manner via several signaling molecules, including FGFs. FGF/FGFR signaling contributes to the skin surface expansion in childhood or during wound healing, and skin protection from UV light damage. Aberrant FGF/FGFR signaling has been implicated in many disorders, including cancer. In melanoma cells, the FGFR expression is low, probably because of the strong endogenous mutation-driven constitutive activation of the downstream mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-ERK) signaling pathway. FGFR1 is exceptional as it is expressed in the majority of melanomas at a high level. Melanoma cells that acquired the capacity to synthesize FGFs can influence the neighboring cells in the tumor niche, such as endothelial cells, fibroblasts, or other melanoma cells. In this way, FGF/FGFR signaling contributes to intratumoral angiogenesis, melanoma cell survival, and development of resistance to therapeutics. Therefore, inhibitors of aberrant FGF/FGFR signaling are considered as drugs in combination treatment. The ongoing LOGIC-2 phase II clinical trial aims to find out whether targeting the FGF/FGFR signaling pathway with BGJ398 may be a good therapeutic strategy in melanoma patients who develop resistance to v-Raf murine sarcoma viral oncogene homolog B (BRAF)/MEK inhibitors.
Fibroblast Growth Factor Receptor Functions in Glioblastoma.
Jimenez-Pascual Ana,Siebzehnrubl Florian A
Glioblastoma is the most lethal brain cancer in adults, with no known cure. This cancer is characterized by a pronounced genetic heterogeneity, but aberrant activation of receptor tyrosine kinase signaling is among the most frequent molecular alterations in glioblastoma. Somatic mutations of fibroblast growth factor receptors () are rare in these cancers, but many studies have documented that signaling through FGFRs impacts glioblastoma progression and patient survival. Small-molecule inhibitors of FGFR tyrosine kinases are currently being trialed, underlining the therapeutic potential of blocking this signaling pathway. Nevertheless, a comprehensive overview of the state of the art of the literature on FGFRs in glioblastoma is lacking. Here, we review the evidence for the biological functions of FGFRs in glioblastoma, as well as pharmacological approaches to targeting these receptors.
Investigational fibroblast growth factor receptor 2 antagonists in early phase clinical trials to treat solid tumors.
Wang Dan,Yang Li,Yu Weina,Zhang Yi
Expert opinion on investigational drugs
: Fibroblast growth factor receptor 2 (FGFR2) is a highly conserved transmembrane tyrosine kinase receptor. FGFR2 dysregulation occurs in numerous human solid tumors and overexpression is closely associated with tumor progression. FGFR2 has recently been reported as a therapeutic target for cancer. Several targeted therapies are being investigated to disrupt FGFR2 activity; these include multi-target tyrosine kinase inhibitors (TKIs), pan-FGFR targeted TKIs and FGFR2 monoclonal antibodies. : This review examines FGFR2 regulation and function in cancer and its potential as a target for cancer treatment. : Highly specific FGFR2 blockers have not yet been developed and moreover, resistance to FGFR2-targeted therapies is a challenge. More sophisticated patient selection strategies would help improve FGFR2-targeted therapies and combination therapy is considered the most promising approach for cancer patients with FGFR2 alterations.
Fibroblast growth factor receptor inhibitors: patent review (2015-2019).
Marseglia Giuseppe,Lodola Alessio,Mor Marco,Castelli Riccardo
Expert opinion on therapeutic patents
: fibroblast growth factor receptors (FGFRs) are a family of tyrosine-kinase receptors whose signaling cascade regulates cellular proliferation, differentiation, and survival. Deregulation of the FGFR pathway is recognized as a driving factor in tumor development. On this basis, FGFR is an attractive target for anti-cancer small-molecule therapeutic agents.: This review summarizes patent and literature publications spanning from 2015 to 2019 pertaining to small-molecule FGFR kinase inhibitors.: The first generation of non-covalent FGFR inhibitors is characterized by a broad spectrum of activity and a relatively high toxicity profile. The second generation of FGFR inhibitors shows higher selectivity and a more favorable toxicity profile, but the clinical use appears restricted only to small subsets of cancers strongly dependent on FGFR signaling. Nevertheless, erdafitinib has been approved for the treatment of metastatic urothelial carcinoma, becoming the first marketed selective FGFR inhibitor. The insurgence of mutant kinases, resistant to available therapies, has led to the development of irreversible FGFR inhibitors. The adoption of safer and more selective covalent inhibitors might supersede reversible inhibitors in specific therapeutic areas. Alternative strategies, such as FGF trapping by protein or small-molecule therapeutics, deserve attention and further investigations to unravel their potential.
The role of fibroblast growth factor receptor (FGFR) protein-tyrosine kinase inhibitors in the treatment of cancers including those of the urinary bladder.
The human fibroblast growth factor family consists of 22 factors and five transmembrane receptors. Of the 22 factors, eighteen are secreted while four of them function exclusively within the cell. Four of the fibroblast growth factor receptors (FGFRs) possess intracellular protein-tyrosine kinase activity while the fifth (FGFRL1) has a short 105-residue intracellular non-enzymatic component. The FGFR protein kinase domain consists of a bi-lobed structure that is similar to that of all other protein kinases. FGFR gene alterations occur in a wide variety of cancers including those of the urinary bladder, breast, ovary, prostate, endometrium, lung, and stomach. The majority (66 %) of FGFR gene alterations involve gene amplifications, followed by mutations (26 %), and rearrangements that produce fusion proteins (8 %). Erdafitinib was the first orally effective FGFR antagonist approved by the FDA (2019) for the treatment of advanced cancer, that of the urinary bladder. FGF23 suppresses phosphate reabsorption in the proximal tubules of the kidney; FGF23 blockade allows phosphate reabsorption to occur and leads to elevated serum phosphate levels. Erdafitinib and several other, but not all, FGFR antagonists produce hyperphosphatemia. Erdafitinib binds to an inactive DGF-D conformation of FGFR1 and is classified as a type I½ inhibitor. Similarly, dovitinib, AZD4547, CH5183284, infigratinib, lenvatinib, LY2874455, and lucitanib are type I½ inhibitors. The inactive conformations contain an autoinhibitory brake that is made up of three main residues: an asparagine (N) within the αC-β4 back loop, a glutamate (E) corresponding to the second hinge residue, and a lysine (K) in the β8-strand (the NEK triad). PDGFRα/β, Kit, CSF1R, VEGFR1/2/3, Flt3, Tek, and Tie protein kinases are also regulated by a similar autoinhibitory brake mechanism. Ponatinib binds to FGFR4 in a DFG-D conformation and is classified as a type II inhibitor. Futibatinib, roblitinib, H3B-6527, fisogatinib, and PRN1371 bind covalently to their FGFR target and are classified as type VI inhibitors. Nintedanib, pazopanib, pemigatinib, rogaratinib, fisogatinib, and PRN1371 are FGFR inhibitors lacking drug-enzyme crystal structures. All of the aforementioned FGFR antagonists are orally effective. The development of FGFR inhibitors has lagged behind those of other receptor protein-tyrosine kinases. However, the FDA approval of erdafitinib for the treatment of urinary bladder cancers may stimulate additional work targeting the many other FGFR-driven neoplasms.
The future of bladder cancer therapy: Optimizing the inhibition of the fibroblast growth factor receptor.
Morales-Barrera Rafael,Suárez Cristina,González Macarena,Valverde Claudia,Serra Ester,Mateo Joaquín,Raventos Carles,Maldonado Xavier,Morote Juan,Carles Joan
Cancer treatment reviews
Therapeutic options for metastatic bladder cancer (BC) have seen minimal evolution over the past 30 years, with platinum-based chemotherapy remaining the mainstay of standard of care for metastatic BC. Recently, five immune checkpoint inhibitors (ICIs) have been approved by the FDA as second-line therapy, and two ICIs are approved as first-line treatment in selected patients. Molecular alterations of muscle-invasive bladder cancer (MIBC) have been reported by The Cancer Genome Atlas. About 15% of patients with MIBC have molecular alterations in the fibroblast growth factor (FGF) axis. Several ongoing trials are testing novel FGF receptor (FGFR) inhibitors in patients with FGFR genomic aberrations. Recently, erdafitinib, a pan-FGFR inhibitor, was approved by the FDA in patients with metastatic BC who have progressed on platinum-based chemotherapy. We reviewed the literature over the last decade and provide a summary of current knowledge of FGF signaling, and the prognosis associated with FGFR mutations in BC. We cover the role of FGFR inhibition with non-selective and selective tyrosine kinase inhibitors as well as novel agents in metastatic BC. Efficacy and safety data including insights from mechanism-based toxicity are reported for selected populations of metastatic BC with FGFR aberrations. Current strategies to managing resistance to anti-FGFR agents is addressed, and the importance of developing reliable biomarkers as the therapeutic landscape moves towards an individualized therapeutic approach.
Fibroblast Growth Factor Receptor (FGFR) Inhibitors in Urothelial Cancer.
Garje Rohan,An Josiah,Obeidat Mohammad,Kumar Kranthi,Yasin Hesham A,Zakharia Yousef
Dysregulated fibroblast growth factor receptor (FGFR) signaling is associated with several cancers, including urothelial carcinoma. Preclinical studies with FGFR inhibitors have shown significant antitumor activity, which has led to clinical evaluation of multiple FGFR inhibitors. Recently, erdafitinib was approved by the U.S. Food and Drug Administration for advanced urothelial carcinoma with FGFR gene alterations as the first molecularly targeted therapy. Additional ongoing clinical trials with other types of FGFR inhibitors have shown encouraging results. This review summarizes the oncogenic signaling of FGFR alterations, completed and ongoing clinical trials of FGFR inhibitors, and resistance patterns. IMPLICATIONS FOR PRACTICE: Dysregulated fibroblast growth factor receptor (FGFR) signaling is associated with several cancers, including urothelial carcinoma. Preclinical studies with FGFR inhibitors have shown significant antitumor activity, which has led to clinical evaluation of multiple FGFR inhibitors. Most recently, erdafitinib was approved by the U.S. Food and Drug Administration for advanced urothelial carcinoma with FGFR gene alterations as the first molecularly targeted therapy. Additional ongoing clinical trials with other types of FGFR inhibitors have shown encouraging results. This review summarizes the oncogenic signaling of FGFR alterations, completed and ongoing clinical trials of FGFR inhibitors, and resistance patterns.
Therapeutic implications of fibroblast growth factor receptor inhibitors in a combination regimen for solid tumors.
Luo Hong,Zhang Tao,Cheng Peng,Li Dong,Ogorodniitchouk Oleksandr,Lahmamssi Chaimaa,Wang Ge,Lan Meiling
A number of novel drugs targeting the fibroblast growth factor receptor (FGFR) signaling pathway have been developed, including mostly tyrosine kinase inhibitors, selective inhibitors or monoclonal antibodies. Multiple preclinical and clinical studies have been conducted worldwide to ascertain their effects on diverse solid tumors. Drugs, such as lenvatinib, dovitinib and other non-specific FGFR inhibitors, widely used in clinical practice, have been approved by the Food and Drug Administration for cancer therapy, although the majority of drugs remain in preclinical tests or clinical research. The resistance to a single agent for FGFR inhibition with synthetic lethal action may be overcome by a combination of therapeutic approaches and FGFR inhibitors, which could also enhance the sensitivity to other therapeutics. Therefore, the aim of the present review is to describe the pharmacological characteristics of FGFR inhibitors that may be combined with other therapeutic agents and the preclinical data supporting their combination. Additionally, their clinical implications and the remaining challenges for FGFR inhibitor combination regimens are discussed.