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Tumor Suppressors Condition Differential Responses to the Selective CDK2 Inhibitor BLU-222
Adam P Dommer1, Vishnu Kumarasamy1, Jianxin Wang1
1Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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.
Insights
The CDK2 inhibitor BLU-222 shows promise in breast and ovarian cancers by halting cell proliferation. Sensitivity is linked to specific gene expression, suggesting a precision medicine approach for combination therapies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Cyclin-dependent kinase 2 (CDK2) inhibitors are emerging as potential cancer treatments.
- Combination therapies may enhance the efficacy of existing therapeutic agents.
- Understanding response mechanisms is crucial for optimizing CDK2 inhibitor use.
Purpose of the Study:
- To evaluate the selective CDK2 inhibitor BLU-222 in ovarian and breast cancer models.
- To identify mechanisms of response and resistance to CDK2 inhibition.
- To explore combinatorial strategies for enhancing CDK2 inhibitor effectiveness.
Main Methods:
- Utilized cellular CDK activity sensors to assess sensitivity to CDK4/6 and CDK2 inhibition.
- Administered BLU-222 to cancer models and monitored cell-cycle progression and proliferation.
- Conducted combinatorial drug screens to identify synergistic and antagonistic drug relationships.
- Analyzed clinical gene and protein expression data for response biomarkers.
Main Results:
- BLU-222 inhibited proliferation by affecting both G1 and G2 phases of the cell cycle, unlike CDK4/6 inhibitors.
- Sensitivity to BLU-222 was mediated by the RB tumor suppressor and linked to cyclin E1 and P16INK4A expression.
- Approximately 25% of ovarian cancers showed molecular signatures predictive of strong sensitivity to CDK2 inhibition.
- Combinatorial screens identified synergistic (e.g., CDK4/6 inhibitors) and antagonistic (e.g., WEE1 inhibitors) interactions.
Conclusions:
- BLU-222 demonstrates preclinical efficacy in ovarian and breast cancers.
- Coordinate expression of cyclin E1 and P16INK4A predicts sensitivity to CDK2 inhibition.
- A precision strategy utilizing CDK2 inhibitors, potentially in combination, is advanced for these cancers.
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