Profiling the Activity of the Potent and Highly Selective CDK2 Inhibitor BLU-222 Reveals Determinants of Response in CCNE1-Aberrant Ovarian and Endometrial Tumors.

ABSTRACT: 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 pacl

SUBMITTER: House NC 

PROVIDER: S-EPMC11967718 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature