Nealia House

CDK2 regulates collapsed replication fork repair in CCNE1-amplified ovarian cancer cells via homologous recombination

Abstract CCNE1 amplification is a common alteration in high-grade serous ovarian cancer and occurs in 15–20% of these tumors. These amplifications are mutually exclusive with homologous recombination deficiency, and, as they have intact homologous recombination, are intrinsically resistant to poly (ADP-ribose) polymerase inhibitors or chemotherapy agents. Understanding the molecular mechanisms that lead to this mutual exclusivity may reveal therapeutic vulnerabilities that could be leveraged in the clinic in this still underserved patient population. Here, we demonstrate that CCNE1-amplified high-grade serous ovarian cancer cells rely on homologous recombination to repair collapsed replication forks. Cyclin-dependent kinase 2, the canonical partner of cyclin E1, uniquely regulates homologous recombination in this genetic context, and as such cyclin-dependent kinase 2 inhibition synergizes with DNA damaging agents in vitro and in vivo. We demonstrate that combining a selective cyclin-dependent kinase 2 inhibitor with a DNA damaging agent could be a powerful tool in the clinic for high-grade serous ovarian cancer.

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 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