Cyclin E1 overexpression sensitizes ovarian cancer cells to WEE1 and PLK1 inhibition

Abstract

Cyclin E1 (CCNE1) amplification is associated with poor prognosis of ovarian carcinomas across histological subtypes. Inhibitors targeting PLK1 or WEE1 are emerging as promising therapeutic agents for cancer treatment that disrupt the critical G2/M checkpoint, leading to cancer cell death. However, biomarkers that predict the response to these inhibitors are not well defined. Here, we evaluated the efficacy of the PLK1 inhibitor, volasertib, and the WEE1 inhibitor, adavosertib, along with the biomarker potential of cyclin E1 in ovarian cancer cells. Both inhibitors suppressed the proliferation of cyclin E1-overexpressing cells to a greater extent than that of cells exhibiting low cyclin E1 expression. TP53 silencing did not increase the sensitivity to these inhibitors. In cyclin E1-overexpressing cells, PLK1 inhibition reduced the proportion of cells in the G1 phase and increased those in the G2/M and sub-G1 phases. WEE1 inhibition reduced G1 phase cells without a clear peak in the S-G2/M phase and increased the sub-G1 phase cells. Both inhibitors suppressed the growth of cyclin E1-overexpressing tumors in vivo. Taken together, cyclin E1 overexpression, regardless of TP53 status, may serve as a predictive biomarker for the efficacy of these inhibitors, offering potential personalized treatment strategies for ovarian cancer.