BLU-222 is an investigational, potent, highly selective, orally bioavailable cyclin-dependent kinase 2 (CDK2) inhibitor in clinical development. BLU-222 demonstrated robust antitumor activity in select CCNE1-high ovarian and endometrial cancer models. We used a combination of CRISPR whole-genome screens coupled with targeted genetic and pharmacologic approaches in ovarian and endometrial cell lines to identify biological determinants to predict BLU-222 monotherapy activity. Rb and p16 expression were biomarkers that enriched for CDK2-dependency/BLU-222 sensitivity in CCNE1-overexpressed, nonamplified cells. Furthermore, intact Rb and low p16 expression predicted a BLU-222 and CDK4/6 inhibitor combination response. BLU-222 demonstrated robust activity in combination with carboplatin or paclitaxel in CCNE1-aberrant models, rendering chemotherapy-resistant tumors strongly sensitive to the combination. These findings demonstrate that response to CDK2 inhibition by BLU-222 can be further predicted using a combinatorial biomarker signature that could refine patient selection criteria in CCNE1-high patients and support clinical development. Significance: The identification of biomarkers of response to the CDK2-selective inhibitor BLU-222 and effective combinations with CDK4/6 inhibitors or chemotherapy could enable precision medicine strategies for CDK2 inhibition in ovarian and endometrial cancer. See related article by Dommer and colleagues, p. 1310.
©2025 The Authors; Published by the American Association for Cancer Research.