Cyclin E1-CDK 2, a potential anticancer target

CCNE1 is one of the most frequent gene amplifications in high grade serous ovarian cancers (HGSOCs), which occurs in at least 20% of HGSOC and in 30% of established ovarian cancer cell lines. Studies with both primary and metastatic ovary tumor specimens further suggest that the abundance of CCNE1 protein expression correlates with tumor progression and predicts a poor prognosis in ovarian cancer patients[1]. It is noted that, CCNE1 is critical for the growth of ovarian cancer cell lines with elevated CCNE1 expression but not cells without CCNE1 overexpression [1]. Furthermore, CCNE1 gene amplification-associated CCNE1 overexpression has been linked to the development of chemo-resistance in ovarian cancer[1]. Thus, accumulated findings implicate that CCNE1 may be a promising therapeutic target for ovary tumors with elevated CCNE1 expression. However, developing small molecules to target CCNE1 directly is unlikely, because CCNE1 acts as a regulatory subunit of cyclindependent kinase (Cdk) complex rather than as an enzyme or receptor. It is well known that CCNE1 mainly coordinates with Cdk2 to facilitate G1/S progression of cell cycle. In ovary tumors, elevated CCNE1 level is often correlated with higher Cdk2 expression and most of CCNE1associated tumor promoting effects require the participation of Cdk2. Thus, targeting Cdk2 may be an attractive alternative given the current availability of small molecule Cdk2 inhibitors. SNS-032 (BMS387032) is a selective inhibitor of CDK2, and has been evaluated in Phase I study for patients with either chronic lymphocytic leukemia or multiple myeloma, as well as clinical safety assessment for the treatment of select advanced solid tumors. We showed that ovarian cancer cells with elevated CCNE1 expression are at least 40 times more sensitive to SNS-032 than those without CCNE1 overexpression. Moreover, we demonstrated that SNS-032 effectively suppresses the tumorigenicity of ovarian cancer cells by prolonging the survival of animals bearing tumors derived from ovarian cancer cells with elevated CCNE1 expression and inhibiting peritoneal metastatic colonization. These results suggest that ovary tumors with elevated CCNE1 expression may be staged for Cdk2-targeted therapy. Editorial