p16 expression confers sensitivity to CDK2 inhibitors.
Biorxiv : the Preprint Server for Biology
|February 24, 2025
Summary
The tumor suppressor p16 inhibits CDK4/6, enhancing sensitivity to CDK2 inhibitors in ovarian cancers. This finding identifies p16 as a potential biomarker for predicting patient response to CDK2-targeted cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cell Cycle Regulation
Background:
- Cyclin-Dependent Kinase 2 (CDK2) is a key target for cancer therapy, but its inhibition can be circumvented by compensatory CDK4/6 activity.
- This compensatory mechanism allows cancer cells to maintain proliferation and CDK2 reactivation, limiting the efficacy of CDK2 inhibitors.
Purpose of the Study:
- To investigate the hypothesis that sensitivity to CDK2 inhibition is associated with the absence of CDK4/6-mediated compensation.
- To identify potential biomarkers for predicting patient response to CDK2 inhibitors in ovarian cancer.
Main Methods:
- Analysis of ovarian cancer cell lines co-expressing Cyclin E1 and the tumor suppressor p16.
- Assessment of sensitivity to CDK2 inhibitors in cells with and without p16.
- Multiplexed immunofluorescence staining of 225 ovarian patient tumors to evaluate Cyclin E1 and p16 expression levels.
Main Results:
- Ovarian cancer cells expressing p16 demonstrated heightened sensitivity to CDK2 inhibitors.
- Depletion of p16 significantly increased resistance to CDK2 inhibitors.
- At least 18% of analyzed ovarian tumors showed high expression of both Cyclin E1 and p16.
Conclusions:
- The presence of p16, which inhibits CDK4/6, is linked to increased sensitivity to CDK2 inhibitors in ovarian cancer.
- p16 may serve as a predictive biomarker for identifying ovarian cancer patients who will benefit from CDK2 inhibitor therapy.
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