ArticleCancer research2025
Tumor Suppressors Condition Differential Responses to the Selective CDK2 Inhibitor BLU-222.
Article in Cancer research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Castration-resistant prostate cancer cells are addicted to the high activity of cyclin-dependent kinase 2.Molecular oncology · 2026Article
- An Integrated Computational Workflow for Discovering Alkaloid-Derived Ligands of Cyclin-Dependent Kinase 2.Pharmaceuticals (Basel, Switzerland) · 2026Article
- The evolving landscape of CDK inhibitor use in breast cancer therapy and beyond.Nature reviews. Drug discovery · 2026Review
- Cyclin E modulates vulnerability to CDC7 kinase inhibition.Oncogenesis · 2026Article
- Emerging Strategies to Inhibit the G1/S Transition for Cancer Therapy.Cancer research · 2026Review
- CDK2 inhibitor BLU-222 synergizes with CDK4/6 inhibitors in drug resistant breast cancers through p21/p27 induction.Nature communications · 2026Article
- Therapeutic advances in HR+/HER2- advanced breast cancer after failure of CDK4/6 inhibitor therapy.Frontiers in oncology · 2026Review
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- CDK2 inhibition enhances CDK4/6 inhibitor antitumor activity in comprehensive breast cancer PDX model screen.NPJ breast cancer · 2025Article
- Intrinsic RB activation induces tumoral and stromal anti-tumor responses that limit triple-negative breast cancer.NPJ breast cancer · 2025Article
- p16 expression confers sensitivity to CDK2 inhibitors in cyclin E1-driven ovarian cancers.Science signaling · 2025Article
- Multi-omics pan-cancer profiling of CDK2 andRSC advances · 2025Article
- Therapeutic benefits of maintaining CDK4/6 inhibitors and incorporating CDK2 inhibitors beyond progression in breast cancer.bioRxiv : the preprint server for biology · 2025Article
- Targeting CDK2 for cancer therapy.Cell reports · 2025Review
- From cell cycle control to cancer therapy: exploring the role of CDK1 and CDK2 in tumorigenesis.Medical oncology (Northwood, London, England) · 2025Review
- Article
- Cell Cycle Plasticity and Heterogeneity: An Underappreciated Feature of Cancer and Treatment Response.Cancer heterogeneity and plasticity · 2025Article
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Authors and funding
9 authors.
Funding
Abstract
Cyclin-dependent kinase 2 (CDK2) inhibitors have recently been developed and have entered clinical trials. Combination approaches can help broaden the use of therapeutic agents and establish more effective treatments. Here, we evaluated the selective CDK2 inhibitor BLU-222 for mechanisms of response in the context of ovarian and breast cancer models. Sensors of cellular CDK activity indicated that sensitivity to either CDK4/6 or CDK2 inhibition was 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 reenter the cell cycle upon drug withdrawal. The antiproliferative strength and impact on G1-S versus G2-M accumulation was mediated by the RB tumor suppressor. 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 analyses revealed a positive correlation between cyclin E1 and P16INK4A and identified 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. Significance: The CDK2-specific inhibitor BLU-222 shows preclinical efficacy in breast and ovarian cancer with select determinants of response and holds promise in combinatorial strategies. See related article by House and colleagues, p. 1297.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.