PI3K and MAPK Pathways as Targets for Combination with the Pan-HER Irreversible Inhibitor Neratinib in HER2-Positive Breast Cancer and TNBC by Kinome RNAi Screening.
Lee Jangsoon,Liu Huey,Pearson Troy,Iwase Toshiaki,Fuson Jon,Lalani Alshad S,Eli Lisa D,Diala Irmina,Tripathy Debu,Lim Bora,Ueno Naoto T
Biomedicines
Human epidermal growth factor receptor (EGFR) 2 (HER2) is overexpressed/amplified in about 25% of all breast cancers, and EGFR is overexpressed in up to 76% and amplified in up to 24% of triple-negative breast cancers (TNBC). Here, we aimed to identify inhibitors that may enhance the anti-tumor activity of neratinib for HER2+ breast cancer and TNBC. By conducting a non-biased high-throughput RNA interference screening, we identified PI3K/AKT/mTOR and MAPK as two potential inhibitory synergistic canonical pathways. We confirmed that everolimus (mTOR inhibitor) and trametinib (MEK inhibitor) enhances combinatorial anti-proliferative effects with neratinib under anchorage-independent growth conditions ( < 0.05). Compared to single agent neratinib, the combination therapies significantly enhanced tumor growth inhibition in both SUM190 HER2+ breast cancer (neratinib plus everolimus, 77%; neratinib plus trametinib, 77%; < 0.0001) and SUM149 TNBC (neratinib plus everolimus, 71%; neratinib plus trametinib, 81%; < 0.0001) xenograft models. Compared to single-agent neratinib, everolimus, or trametinib, both everolimus plus neratinib and trametinib plus neratinib significantly suppressed proliferation marker Ki67 and enhanced antitumor efficacy by activating the apoptosis pathway shown by increased Bim and cleaved-PARP expression. Taken together, our data justify new neratinib-based combinations for both HER2+ breast cancer and TNBC.
10.3390/biomedicines9070740
PI3K inhibitors are finally coming of age.
Nature reviews. Drug discovery
Overactive phosphoinositide 3-kinase (PI3K) in cancer and immune dysregulation has spurred extensive efforts to develop therapeutic PI3K inhibitors. Although progress has been hampered by issues such as poor drug tolerance and drug resistance, several PI3K inhibitors have now received regulatory approval - the PI3Kα isoform-selective inhibitor alpelisib for the treatment of breast cancer and inhibitors mainly aimed at the leukocyte-enriched PI3Kδ in B cell malignancies. In addition to targeting cancer cell-intrinsic PI3K activity, emerging evidence highlights the potential of PI3K inhibitors in cancer immunotherapy. This Review summarizes key discoveries that aid the clinical translation of PI3Kα and PI3Kδ inhibitors, highlighting lessons learnt and future opportunities.
10.1038/s41573-021-00209-1
Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer.
Seminars in cancer biology
Cancer is the second leading cause of human death globally. PI3K/Akt/mTOR signaling is one of the most frequently dysregulated signaling pathways observed in cancer patients that plays crucial roles in promoting tumor initiation, progression and therapy responses. This is largely due to that PI3K/Akt/mTOR signaling is indispensable for many cellular biological processes, including cell growth, metastasis, survival, metabolism, and others. As such, small molecule inhibitors targeting major kinase components of the PI3K/Akt/mTOR signaling pathway have drawn extensive attention and been developed and evaluated in preclinical models and clinical trials. Targeting a single kinase component within this signaling usually causes growth arrest rather than apoptosis associated with toxicity-induced adverse effects in patients. Combination therapies including PI3K/Akt/mTOR inhibitors show improved patient response and clinical outcome, albeit developed resistance has been reported. In this review, we focus on revealing the mechanisms leading to the hyperactivation of PI3K/Akt/mTOR signaling in cancer and summarizing efforts for developing PI3K/Akt/mTOR inhibitors as either mono-therapy or combination therapy in different cancer settings. We hope that this review will facilitate further understanding of the regulatory mechanisms governing dysregulation of PI3K/Akt/mTOR oncogenic signaling in cancer and provide insights into possible future directions for targeted therapeutic regimen for cancer treatment, by developing new agents, drug delivery systems, or combination regimen to target the PI3K/Akt/mTOR signaling pathway. This information will also provide effective patient stratification strategy to improve the patient response and clinical outcome for cancer patients with deregulated PI3K/Akt/mTOR signaling.
10.1016/j.semcancer.2021.06.019
PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside.
Alzahrani Ali S
Seminars in cancer biology
Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is one of the major cellular signaling pathways that plays an important role in basic intracellular functions. The PI3K/Akt/mTOR pathway regulates cell proliferation, growth, cell size, metabolism, and motility. Component genes of this pathway have been extensively studied and found to be commonly activated in human cancer. Inhibition of this pathway has been shown to lead to regression of human tumors and has been studied in preclinical setup and evaluated in many clinical trials at various levels. Some inhibitors of this pathway are approved by the Food and Drug Administration after their potency and safety have been shown in clinical trials. This review discusses the recent trends in exploiting the PI3K/Akt/mTOR pathway towards the molecular targeted therapy using small molecule inhibitors in human cancer.
10.1016/j.semcancer.2019.07.009
Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisib.
Rao V Koneti,Webster Sharon,Dalm Virgil A S H,Šedivá Anna,van Hagen P Martin,Holland Steven,Rosenzweig Sergio D,Christ Andreas D,Sloth Birgitte,Cabanski Maciej,Joshi Aniket D,de Buck Stefan,Doucet Julie,Guerini Danilo,Kalis Christoph,Pylvaenaeinen Ilona,Soldermann Nicolas,Kashyap Anuj,Uzel Gulbu,Lenardo Michael J,Patel Dhavalkumar D,Lucas Carrie L,Burkhart Christoph
Blood
Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase δ (PI3Kδ) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kδ syndrome [APDS]). Knowing the genetic etiology of APDS afforded us the opportunity to explore PI3Kδ inhibition as a precision-medicine therapy. Here, we report in vitro and in vivo effects of inhibiting PI3Kδ in APDS. Treatment with leniolisib (CDZ173), a selective PI3Kδ inhibitor, caused dose-dependent suppression of PI3Kδ pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110δ variants and in T-cell blasts derived from patients. A clinical trial with 6 APDS patients was conducted as a 12-week, open-label, multisite, within-subject, dose-escalation study of oral leniolisib to assess safety, pharmacokinetics, and effects on lymphoproliferation and immune dysregulation. Oral leniolisib led to a dose-dependent reduction in PI3K/AKT pathway activity assessed ex vivo and improved immune dysregulation. We observed normalization of circulating transitional and naive B cells, reduction in PD-1CD4 and senescent CD57CD4 T cells, and decreases in elevated serum immunoglobulin M and inflammatory markers including interferon γ, tumor necrosis factor, CXCL13, and CXCL10 with leniolisib therapy. After 12 weeks of treatment, all patients showed amelioration of lymphoproliferation with lymph node sizes and spleen volumes reduced by 39% (mean; range, 26%-57%) and 40% (mean; range, 13%-65%), respectively. Thus, leniolisib was well tolerated and improved laboratory and clinical parameters in APDS, supporting the specific inhibition of PI3Kδ as a promising new targeted therapy in APDS and other diseases characterized by overactivation of the PI3Kδ pathway. This trial was registered at www.clinicaltrials.gov as #NCT02435173.
10.1182/blood-2017-08-801191
Pictilisib PI3Kinase inhibitor (a phosphatidylinositol 3-kinase [PI3K] inhibitor) plus paclitaxel for the treatment of hormone receptor-positive, HER2-negative, locally recurrent, or metastatic breast cancer: interim analysis of the multicentre, placebo-controlled, phase II randomised PEGGY study.
Vuylsteke P,Huizing M,Petrakova K,Roylance R,Laing R,Chan S,Abell F,Gendreau S,Rooney I,Apt D,Zhou J,Singel S,Fehrenbacher L
Annals of oncology : official journal of the European Society for Medical Oncology
BACKGROUND:Approximately 40% of hormone receptor-positive, HER2-negative breast cancers (BCs) are associated with activating mutations of the phosphatidylinositol 3-kinase (PI3K) pathway. Pictilisib, a potent and highly specific class I pan-PI3K inhibitor, demonstrated preclinical activity in BC cell lines and may potentiate the effect of taxanes, benefiting patients with or without aberrant activation of the PI3K pathway. PEGGY (NCT01740336), a randomised, placebo-controlled phase II trial, examined whether pictilisib augments the anti-tumour activity of paclitaxel in patients with hormone receptor-positive, HER2-negative locally recurrent or metastatic BC (mBC). We report results from the protocol-specified interim analysis. PATIENTS AND METHODS:One hundred and eighty-three eligible patients were randomised (1:1) to receive paclitaxel (90 mg/m weekly for 3 weeks in every 28-day cycle) with either 260 mg pictilisib or placebo (daily on days 1-5 every week). The primary end point was progression-free survival (PFS) in the intention-to-treat (ITT) population and patients with PIK3CA-mutated tumours. Secondary end points included overall response rate (ORR), duration of response, and safety. RESULTS:In the ITT population, the median PFS was 8.2 months with pictilisib (n = 91) versus 7.8 months with placebo (n = 92) [hazard ratio (HR) for progression or death, 0.95; 95% confidence interval (CI) 0.62-1.46; P = 0.83]. In patients with PIK3CA-mutated tumours, the median PFS was 7.3 months for pictilisib (n = 32) versus 5.8 months with placebo (n = 30) (HR, 1.06; 95% CI 0.52-2.12; P = 0.88). ORR was similar between treatment arms. The safety profile of pictilisib was consistent with previous reports, with no new safety signals. Proportions of patients with grade ≥3 adverse events (AEs), serious AEs, and dose reductions/discontinuations due to AEs were higher with pictilisib. CONCLUSIONS:PEGGY did not meet its primary end point, revealing no significant benefit from adding pictilisib to paclitaxel for patients with hormone receptor-positive, HER2-negative locally recurrent or mBC. CLINICAL TRIAL NUMBER:NCT01740336.
10.1093/annonc/mdw320
Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.
Donnella Hayley J,Webber James T,Levin Rebecca S,Camarda Roman,Momcilovic Olga,Bayani Nora,Shah Khyati N,Korkola James E,Shokat Kevan M,Goga Andrei,Gordan John D,Bandyopadhyay Sourav
Nature chemical biology
Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer.
10.1038/s41589-018-0081-9
Imbalance of the reciprocally inhibitory loop between the ubiquitin-specific protease USP43 and EGFR/PI3K/AKT drives breast carcinogenesis.
He Lin,Liu Xinhua,Yang Jianguo,Li Wanjin,Liu Shumeng,Liu Xujun,Yang Ziran,Ren Jie,Wang Yue,Shan Lin,Guan Chengjian,Pei Fei,Lei Liandi,Zhang Yu,Yi Xia,Yang Xiaohan,Liang Jing,Liu Rong,Sun Luyang,Shang Yongfeng
Cell research
Hyperactivation of EGFR/PI3K/AKT is a prominent feature of various human cancers. Thus, understanding how this molecular cascade is balanced is of great importance. We report here that the ubiquitin-specific protease USP43 is physically associated with the chromatin remodeling NuRD complex and catalyzes H2BK120 deubiquitination. Functionally this coordinates the NuRD complex to repress a cohort of genes, including EGFR, which are critically involved in cell proliferation and carcinogenesis. We show that USP43 strongly suppresses the growth and metastasis of breast cancer in vivo. Interestingly, USP43 also exists in the cytoplasm, where it is phosphorylated by AKT, enabling its binding to the 14-3-3β/ε heterodimer and sequestration in the cytoplasm. Significantly, hyperactivation of EGFR/PI3K/AKT in breast cancer is associated with the cytoplasmic retention of USP43 and thus, the inhibition of its transcriptional regulatory function. Moreover, cancer-associated mutations of USP43 affect its subcellular localization and/or epigenetic regulatory functions. Nuclear USP43 is significantly reduced in breast carcinomas and is associated with EGFR accumulation and AKT hyperactivation. A low level of nuclear USP43 correlates with higher histologic grades and poor prognosis. Our study identifies USP43 to be an H2BK120 deubiquitinase and a potential tumor suppressor and reveals a reciprocally inhibitory loop between USP43 and EGFR/PI3K/AKT, whose imbalance drives breast carcinogenesis.
10.1038/s41422-018-0079-6
Alpelisib Plus Fulvestrant in PIK3CA-Altered and PIK3CA-Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer: A Phase 1b Clinical Trial.
Juric Dejan,Janku Filip,Rodón Jordi,Burris Howard A,Mayer Ingrid A,Schuler Martin,Seggewiss-Bernhardt Ruth,Gil-Martin Marta,Middleton Mark R,Baselga José,Bootle Douglas,Demanse David,Blumenstein Lars,Schumacher Karl,Huang Alan,Quadt Cornelia,Rugo Hope S
JAMA oncology
Importance:The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in patients with estrogen receptor-positive (ER+), endocrine therapy-resistant breast cancers. Objective:To assess the maximum tolerated dose (MTD), safety, and activity of alpelisib, an oral, PI3Kα-specific inhibitor, plus fulvestrant in patients with ER+ advanced breast cancer (ABC). Design, Setting, and Participants:An open-label, single-arm, phase 1b study of alpelisib plus fulvestrant was conducted at 10 centers in 5 countries. Participants were 87 postmenopausal women with PIK3CA-altered or PIK3CA-wild-type ER+ ABC, whose cancer progressed during or after antiestrogen therapy. The study began enrolling patients October 5, 2010, and the data cutoff was March 22, 2017. Interventions:Escalating doses of alpelisib were administered once daily, starting at 300 mg, plus fixed-dose fulvestrant, 500 mg, in the dose-escalation phase; alpelisib at the recommended phase 2 dose plus fulvestrant in the dose-expansion phase. Main Outcomes and Measures:The primary end point was determination of the MTD of once-daily alpelisib plus fulvestrant. Secondary end points included safety and preliminary activity. Results:From October 5, 2010, to March 22, 2017, 87 women (median age: 58 years [range, 37-79 years]; median of 5 prior lines of antineoplastic therapy) received escalating once-daily doses of alpelisib (300 mg, n = 9; 350 mg, n = 8; 400 mg, n = 70) plus fixed-dose fulvestrant (500 mg). During dose escalation, dose-limiting toxic effects were reported in 1 patient (alpelisib, 400 mg): diarrhea (grade 2), vomiting, fatigue, and decreased appetite (all grade 3). The MTD of alpelisib when combined with fulvestrant was 400 mg once daily, and the recommended phase 2 dose was 300 mg once daily. Overall, the most frequent grade 3/4 adverse events with alpelisib, 400 mg, once daily (≥10% of patients), regardless of causality, were hyperglycemia (19 [22%]) and maculopapular rash (11 [13%]); 9 patients permanently discontinued therapy owing to adverse events. Median progression-free survival at the MTD was 5.4 months (95% CI, 4.6-9.0 months). Median progression-free survival with alpelisib, 300 to 400 mg, once daily plus fulvestrant was longer in patients with PIK3CA-altered tumors (9.1 months; 95% CI, 6.6-14.6 months) vs wild-type tumors (4.7 months; 95% CI, 1.9-5.6 months). Overall response rate in the PIK3CA-altered group was 29% (95% CI, 17%-43%), with no objective tumor responses in the wild-type group. Conclusions and Relevance:Alpelisib plus fulvestrant has a manageable safety profile in patients with ER+ ABC, and data suggest that this combination may have greater clinical activity in PIK3CA-altered vs wild-type tumors. Trial Registration:ClinicalTrials.gov identifier: NCT01219699.
10.1001/jamaoncol.2018.4475
The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer.
Golden Emily,Rashwan Rabab,Woodward Eleanor A,Sgro Agustin,Wang Edina,Sorolla Anabel,Waryah Charlene,Tie Wan Jun,Cuyàs Elisabet,Ratajska Magdalena,Kardaś Iwona,Kozlowski Piotr,Johnstone Elizabeth K M,See Heng B,Duffy Ciara,Parry Jeremy,Lagerborg Kim A,Czapiewski Piotr,Menendez Javier A,Gorczyński Adam,Wasag Bartosz,Pfleger Kevin D G,Curtis Christina,Lee Bum-Kyu,Kim Jonghwan,Cursons Joseph,Pavlos Nathan J,Biernat Wojciech,Jain Mohit,Woo Andrew J,Redfern Andrew,Blancafort Pilar
Nature communications
Adipogenesis associated Mth938 domain containing (AAMDC) represents an uncharacterized oncogene amplified in aggressive estrogen receptor-positive breast cancers. We uncover that AAMDC regulates the expression of several metabolic enzymes involved in the one-carbon folate and methionine cycles, and lipid metabolism. We show that AAMDC controls PI3K-AKT-mTOR signaling, regulating the translation of ATF4 and MYC and modulating the transcriptional activity of AAMDC-dependent promoters. High AAMDC expression is associated with sensitization to dactolisib and everolimus, and these PI3K-mTOR inhibitors exhibit synergistic interactions with anti-estrogens in IntClust2 models. Ectopic AAMDC expression is sufficient to activate AKT signaling, resulting in estrogen-independent tumor growth. Thus, AAMDC-overexpressing tumors may be sensitive to PI3K-mTORC1 blockers in combination with anti-estrogens. Lastly, we provide evidence that AAMDC can interact with the RabGTPase-activating protein RabGAP1L, and that AAMDC, RabGAP1L, and Rab7a colocalize in endolysosomes. The discovery of the RabGAP1L-AAMDC assembly platform provides insights for the design of selective blockers to target malignancies having the AAMDC amplification.
10.1038/s41467-021-22101-7
Targeting the PI3K/AKT/mTOR Pathway for the Treatment of Mesenchymal Triple-Negative Breast Cancer: Evidence From a Phase 1 Trial of mTOR Inhibition in Combination With Liposomal Doxorubicin and Bevacizumab.
Basho Reva K,Gilcrease Michael,Murthy Rashmi K,Helgason Thorunn,Karp Daniel D,Meric-Bernstam Funda,Hess Kenneth R,Herbrich Shelley M,Valero Vicente,Albarracin Constance,Litton Jennifer K,Chavez-MacGregor Mariana,Ibrahim Nuhad K,Murray James L,Koenig Kimberly B,Hong David,Subbiah Vivek,Kurzrock Razelle,Janku Filip,Moulder Stacy L
JAMA oncology
IMPORTANCE:Triple-negative breast cancer (TNBC) classified by transcriptional profiling as the mesenchymal subtype frequently harbors aberrations in the phosphoinositide 3-kinase (PI3K) pathway, raising the possibility of targeting this pathway to enhance chemotherapy response. Up to 30% of mesenchymal TNBC can be classified histologically as metaplastic breast cancer, a chemorefractory group of tumors with a mixture of epithelial and mesenchymal components identifiable by light microscopy. While assays to identify mesenchymal TNBC are under development, metaplastic breast cancer serves as a clinically identifiable surrogate to evaluate potential regimens for mesenchymal TNBC. OBJECTIVE:To assess safety and efficacy of mammalian target of rapamycin (mTOR) inhibition in combination with liposomal doxorubicin and bevacizumab in patients with advanced metaplastic TNBC. DESIGN, SETTING, AND PARTICIPANTS:Phase 1 study with dose escalation and dose expansion at the University of Texas MD Anderson Cancer Center of patients with advanced metaplastic TNBC. Patients were enrolled from April 16, 2009, to November 4, 2014, and followed for outcomes with a cutoff date of November 1, 2015, for data analysis. INTERVENTIONS:Liposomal doxorubicin, bevacizumab, and the mTOR inhibitors temsirolimus or everolimus using 21-day cycles. MAIN OUTCOMES AND MEASURES:Safety and response. When available, archived tissue was evaluated for aberrations in the PI3K pathway. RESULTS:Fifty-two women with metaplastic TNBC (median age, 58 years; range, 37-79 years) were treated with liposomal doxorubicin, bevacizumab, and temsirolimus (DAT) (N = 39) or liposomal doxorubicin, bevacizumab, and everolimus (DAE) (N = 13). The objective response rate was 21% (complete response = 4 [8%]; partial response = 7 [13%]) and 10 (19%) patients had stable disease for at least 6 months, for a clinical benefit rate of 40%. Tissue was available for testing in 43 patients, and 32 (74%) had a PI3K pathway aberration. Presence of PI3K pathway aberration was associated with a significant improvement in objective response rate (31% vs 0%; P = .04) but not clinical benefit rate (44% vs 45%; P > .99). CONCLUSIONS AND RELEVANCE:Using metaplastic TNBC as a surrogate for mesenchymal TNBC, DAT and DAE had notable activity in mesenchymal TNBC. Objective response was limited to patients with PI3K pathway aberration. A randomized trial should be performed to test DAT and DAE for metaplastic TNBC, as well as nonmetaplastic, mesenchymal TNBC, especially when PI3K pathway aberrations are identified.
10.1001/jamaoncol.2016.5281
PI3K/AKT/mTOR pathway inhibitors in triple-negative breast cancer: a review on drug discovery and future challenges.
Khan Mohammad A,Jain Vineet K,Rizwanullah Md,Ahmad Javed,Jain Keerti
Drug discovery today
Triple-negative breast cancer (TNBC) is a highly malignant subtype of breast cancer associated with poor prognosis. Although conventional chemotherapy regimens have shown some effectiveness in early TNBC cases, the outcome in advanced stages is poor. The PI3K/AKT/mTOR pathway is one of the important and active pathways involved in chemoresistance and survival of TNBC. This pathway is speculated to play an important part in malignant transformation and has been considered as a potential molecular target for the design of therapeutic agents to treat TNBC. This review discusses the potentials and drug discovery perspectives of PI3K/AKT/mTOR as a therapeutic target for effective management of TNBC with anticipated challenges.
10.1016/j.drudis.2019.09.001