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The clinical efficacy of CDK2 inhibition in CDK4/6 inhibitor-resistant HR-positive breast cancer is dependent on p53 but independent of RB

ABSTRACT: Patients with hormone receptor-positive metastatic breast cancer (HR+MBC) eventually progress on CDK4/6 inhibition therapy, underscoring an unmet need for novel targeted therapies. The emergence of selective CDK2 inhibitors presents a promising advancement, positioning these agents for early clinical evaluation. Here, we analyzed tumor and liquid biopsies from patients treated with PF-07104091, the most clinically advanced CDK2 inhibitor. CDK2 inhibition monotherapy proved effective in CDK4/6 inhibitor-resistant HR+MBC patients lacking TP53 mutations. Studies in patient-derived cell lines confirmed that CDK2 inhibition efficacy is p53-dependent but unexpectedly revealed its independence from RB. Notably, we observed increased sensitivity to CDK2 inhibition in models resistant to CDK4/6 inhibitors. Unlike CDK4/6 inhibitors, CDK2 inhibition does not activate RB but rather targets DNA replication, accumulating cells in G2/M. Our findings unravel a novel mechanism of cell cycle arrest mediated through CDK2 and advocate the clinical development of CDK2 inhibitors to address resistance to CDK4/6 therapies in HR+MBC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE265952 | GEO | 2026/05/14

REPOSITORIES: GEO

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Differential responses to selective CDK2 inhibitor BLU-222 is conditioned by tumor suppressors

Project description:The selective CDK2 inhibitor BLU-222 was evaluated for mechanisms of response in the context of ovarian and breast cancer models. Using sensors of cellular CDK activity, it was found that sensitivity to either CDK4/6 or CDK2 inhibition is related to the differential dependence on a single CDK for G1/S transition. Unlike CDK4/6 inhibitors, BLU-222 was able to robustly inhibit proliferation through cell cycle inhibition in both G1 and G2 phases. However, it remained possible for cells to re-enter the cell cycle upon drug withdrawal. The anti-proliferative strength and impact on G1/S versus G2/M accumulation was found to be mediated by the RB tumor suppressor, as determined by functional perturbation strategies. To broaden the sensitivity to CDK2 inhibition, combinatorial drug screens were performed that identified both synergistic (e.g., CDK4/6 inhibitors) and antagonistic (e.g., WEE1 inhibitors) relationships. Models that were exceptionally sensitive to CDK2 inhibition displayed coordinate expression of Cyclin E1 and P16INK4A, an endogenous CDK4/6 inhibitor. Functional studies demonstrated that P16INK4A and CDK4/6 activity were key mediators of sensitivity to BLU-222. Clinical gene and protein expression analysis revealed a positive correlation between Cyclin E1 and P16INK4A and that ~25% of ovarian cancers exhibited coordinate expression of Cyclin E, P16INK4A, and RB, indicative of strong sensitivity to CDK2 inhibition. Together, this work advances a precision strategy for the use of CDK2 inhibitors in the context of ovarian and breast cancers.

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2024-10-10 | GSE279160 | GEO

Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle

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Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle [CRISPR]

2025-01-15 | GSE287048 | GEO

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CDK2 inhibition demonstrates RB-independent efficacy in CDK4/6 inhibitor-resistant HR-positive/HER2-negative breast cancer

Project description:CDK2 inhibition demonstrates RB-independent efficacy in CDK4/6 inhibitor-resistant HR-positive/HER2-negative breast cancer

| PRJNA1401876 | ENA

CDK2 inhibition demonstrates RB-independent efficacy in CDK4/6 inhibitor-resistant HR-positive/HER2-negative breast cancer

Project description:CDK2 inhibition demonstrates RB-independent efficacy in CDK4/6 inhibitor-resistant HR-positive/HER2-negative breast cancer

| PRJNA1401875 | ENA

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