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Blocking the cell cycle is a promising avenue for cancer therapy, with cyclin-dependent kinase 2 (CDK2) emerging as a key target. However, in multiple cell types, the activities of CDK4 and CDK6 (CDK4/6) compensate for CDK2 inhibition and sustain tumor cell proliferation, enabling CDK2 reactivation. Thus, we hypothesized that sensitivity to CDK2 inhibition is linked to the absence of this CDK4/6-mediated compensatory mechanism. We found that cyclin E1–driven ovarian cancers often coexpressed the tumor suppressor p16, which inhibited CDK4/6 signaling. Single-cell time-lapse imaging showed that high abundance of p16 conferred increased sensitivity to CDK2 inhibitors, whereas depletion of p16 rendered cells more resistant to CDK2 inhibition through CDK4/6-dependent compensation. Concordantly, acquired resistance to CDK2 inhibitors correlated with reduced p16 and increased cyclin D1 protein abundance. Multiplexed immunofluorescence of 225 ovarian tumors from patients revealed that 18% of the tumors had high cyclin E1 and p16 expression. Thus, p16 may be a useful biomarker for identifying patients most likely to benefit from CDK2 inhibitors.