对CDK2抑制剂敏感与耐药的机制

CDK2 is a core cell-cycle kinase that phosphorylates many substrates to drive progression through the cell cycle. We used several CDK2 inhibitors in clinical development to interrogate CDK2 substrate phosphorylation, cell-cycle progression, and drug adaptation in preclinical models. Whereas CDK1 is known to compensate for loss of CDK2 in Cdk2-/- mice, this is not true for acute inhibition of CDK2. In normal mammary cells and estrogen receptor-positive breast cancer cells, CDK2 inhibition causes a rapid loss of substrate phosphorylation that is rapidly restored by a hard-wired cell-cycle buffering mechanism in which CDK4/6 maintains Rb hyper-phosphorylation, E2F transcriptional activity, and Cyclin A2 expression, enabling re-activation of CDK2. Thus, we hypothesized that sensitivity to CDK2 inhibition is linked to the absence of this CDK4/6-mediated compensatory mechanism. Indeed, we found that Cyclin E1-driven ovarian cancers often co-express the tumor suppressor p16, which inhibits CDK4/6. We show that ovarian cancer cells expressing p16 exhibit heightened sensitivity to CDK2 inhibitors and that depletion of p16 renders them resistant. Multiplexed immunofluorescence of 225 ovarian patient tumors reveals that at least 18% of tumors express high Cyclin E1 and high p16, a group that we expect to be particularly sensitive to CDK2 inhibition. These data further reveal two cell-cycle entry paths that are readily detectable in patient tumors - the canonical CDK4/6-Cyclin D path, and the CDK2-Cyclin E path ‘bypass' path. Thus, p16 may be a useful biomarker for identifying the patients that are most dependent on the CDK2-Cyclin E path and are thus most likely to benefit from CDK2 inhibitors.