The CDK4/6 inhibitor revolution - a game-changing era for breast cancer treatment. Nature reviews. Clinical oncology Cyclin-dependent kinase (CDK) 4/6 inhibition in combination with endocrine therapy is the standard-of-care treatment for patients with advanced-stage hormone receptor-positive, HER2 non-amplified (HRHER2) breast cancer. These agents can also be administered as adjuvant therapy to patients with higher-risk early stage disease. Nonetheless, the clinical success of these agents has created several challenges, such as how to address acquired resistance, identifying which patients are most likely to benefit from therapy prior to treatment, and understanding the optimal timing of administration and sequencing of these agents. In this Review, we describe the rationale for targeting CDK4/6 in patients with breast cancer, including a summary of updated clinical evidence and how this should inform clinical practice. We also discuss ongoing research efforts that are attempting to address the various challenges created by the widespread implementation of these agents. 10.1038/s41571-023-00840-4

Inhibition of CDK4/6 Promotes CD8 T-cell Memory Formation. Cancer discovery CDK4/6 inhibitors are approved to treat breast cancer and are in trials for other malignancies. We examined CDK4/6 inhibition in mouse and human CD8 T cells during early stages of activation. Mice receiving tumor-specific CD8 T cells treated with CDK4/6 inhibitors displayed increased T-cell persistence and immunologic memory. CDK4/6 inhibition upregulated MXD4, a negative regulator of MYC, in both mouse and human CD8 T cells. Silencing of in mouse CD8 T cells demonstrated the importance of this axis for memory formation. We used single-cell transcriptional profiling and T-cell receptor clonotype tracking to evaluate recently activated human CD8 T cells in patients with breast cancer before and during treatment with either palbociclib or abemaciclib. CDK4/6 inhibitor therapy in humans increases the frequency of CD8 memory precursors and downregulates their expression of MYC target genes, suggesting that CDK4/6 inhibitors in patients with cancer may augment long-term protective immunity. SIGNIFICANCE: CDK4/6 inhibition skews newly activated CD8 T cells toward a memory phenotype in mice and humans with breast cancer. CDK4/6 inhibitors may have broad utility outside breast cancer, particularly in the neoadjuvant setting to augment CD8 T-cell priming to tumor antigens prior to dosing with checkpoint blockade.. 10.1158/2159-8290.CD-20-1540

INX-315, a Selective CDK2 Inhibitor, Induces Cell Cycle Arrest and Senescence in Solid Tumors. Cancer discovery Cyclin-dependent kinase 2 (CDK2) is thought to play an important role in driving proliferation of certain cancers, including those harboring CCNE1 amplification and breast cancers that have acquired resistance to CDK4/6 inhibitors (CDK4/6i). The precise impact of pharmacologic inhibition of CDK2 is not known due to the lack of selective CDK2 inhibitors. Here we describe INX-315, a novel and potent CDK2 inhibitor with high selectivity over other CDK family members. Using cell-based assays, patient-derived xenografts (PDX), and transgenic mouse models, we show that INX-315 (i) promotes retinoblastoma protein hypophosphorylation and therapy-induced senescence (TIS) in CCNE1-amplified tumors, leading to durable control of tumor growth; (ii) overcomes breast cancer resistance to CDK4/6i, restoring cell cycle control while reinstating the chromatin architecture of CDK4/6i-induced TIS; and (iii) delays the onset of CDK4/6i resistance in breast cancer by driving deeper suppression of E2F targets. Our results support the clinical development of selective CDK2 inhibitors. SIGNIFICANCE:INX-315 is a novel, selective inhibitor of CDK2. Our preclinical studies demonstrate activity for INX-315 in both CCNE1-amplified cancers and CDK4/6i-resistant breast cancer. In each case, CDK2 inhibition induces cell cycle arrest and a phenotype resembling cellular senescence. Our data support the development of selective CDK2 inhibitors in clinical trials. See related commentary by Watts and Spencer, p. 386. This article is featured in Selected Articles from This Issue, p. 384. 10.1158/2159-8290.CD-23-0954