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p16 expression confers sensitivity to CDK2 inhibitors in cyclin E1-driven ovarian cancers

Chance C Sine1,2, Lotte P Watts1, Brianna Fernandez1

  • 1Department of Biochemistry and BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80303, USA.

Science Signaling
|November 25, 2025
PubMed

Insights

The tumor suppressor p16 inhibits compensatory CDK4/6 signaling, enhancing sensitivity to CDK2 inhibitors in ovarian cancers. High p16 expression may identify patients who benefit from CDK2-targeted therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Cycle Regulation

Background:

  • Targeting cyclin-dependent kinase 2 (CDK2) is a key strategy in cancer therapy.
  • CDK4 and CDK6 (CDK4/6) can compensate for CDK2 inhibition, leading to tumor cell proliferation and resistance.

Purpose of the Study:

  • To investigate the hypothesis that sensitivity to CDK2 inhibition is linked to the absence of CDK4/6-mediated compensatory mechanisms.
  • To identify potential biomarkers for predicting response to CDK2 inhibitors.

Main Methods:

  • Single-cell time-lapse imaging to assess cell sensitivity to CDK2 inhibitors.
  • Analysis of p16 and cyclin D1 protein abundance in relation to CDK2 inhibitor resistance.
  • Multiplexed immunofluorescence on patient-derived ovarian tumors.

Main Results:

  • High p16 expression correlated with increased sensitivity to CDK2 inhibitors by inhibiting CDK4/6 signaling.
  • Depletion of p16 led to resistance via CDK4/6-dependent compensation.
  • Acquired resistance to CDK2 inhibitors was associated with reduced p16 and increased cyclin D1.
  • 18% of ovarian tumors showed high cyclin E1 and p16 expression.

Conclusions:

  • p16 acts as a crucial factor in determining sensitivity to CDK2 inhibitors by modulating CDK4/6 activity.
  • p16 may serve as a predictive biomarker for identifying ovarian cancer patients who will benefit from CDK2 inhibitor therapy.

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