Inhibition of CDK2 reduces EZH2 phosphorylation and reactivates ERα expression in high-grade serous ovarian carcinoma.

The cyclin-dependent kinase 2 (CDK2) inhibitor dinaciclib, a potential anti-cancer drug, has been tested in clinical trials and reported to suppress tumor initiating cells. Our recent study demonstrated that pharmacological inhibition of CDK2 or enhancer of zeste homolog 2 (EZH2) allows re-expression of ERα and converts triple-negative breast cancers (TNBC) to luminal ERα-positive, rendering TNBC cells targetable by tamoxifen. Like TNBC, EZH2 is also commonly overexpressed in ovarian cancers, and overexpression of cyclin E1 gene (CCNE1) and/or amplification of its associated kinase CDK2 gene is present in ovarian tumor specimens, both of which are associated with primary treatment resistance and poor outcome in high-grade serous ovarian cancer (HGSC). We determined whether inhibition of CDK2-mediated phosphorylation of EZH2 activates ERα expression in ERα-negative HGSOC cells, rendering them targetable by hormonal therapy. The specific CDK2 inhibitor repressed phosphorylation of EZH2 at T416, and in turn activated the expression of its downstream target ERα gene (ESR1). We tested the efficacy of the combination of CDK2 inhibitor and tamoxifen and found significant synergistic inhibition. We further demonstrated that CDK2 inhibitor is a more promising agent than EZH2 inhibitor in repressing TNBC and HGSOC due to a feedback increase in CDK2 activity by EZH2 inhibitor. Our results indicated that the combination treatment of CDK2 inhibitor and tamoxifen has the potential to benefit patients with ERα-negative HGSOC. AJCR