Evaluation of CHK1 and WEE1 as Candidate Sensitizers to Cisplatin and Paclitaxel

Abstract

Ovarian cancer is the foremost cause of death from gynecologic malignancies in the developed world. The American Cancer Society estimated 22,280 new cases in 2012 and 15,500 deaths. The majority of patients with advanced ovarian cancer relapse from primary treatment and develop drug-resistant disease. The mechanisms underlying drug-resistance are poorly understood. Inhibition of CHK1, a cell cycle G2/M checkpoint kinase has previously been shown to have a synergistic effect with cisplatin in reducing ovarian cancer cell viability. Additional mediators of the G2/M checkpoint have also been found to potentiate the effect of cisplatin and paclitaxel. We chose to evaluate the role of G2/M checkpoint kinases Chk1 and Wee1 and hypothesized that blockade of these kinases would increase the efficacy of cisplatin and paclitaxel either synergistically or additively in the A2780 ovarian cancer cell line model. We determined whether inhibition of CHK1 or WEE1 resulted in an additive or synergistic cytotoxicity in A2780 cells using siRNA technology and specific inhibition using pharmacologic agents. siRNA silencing of CHK1 or WEE1 resulted in an additive effect with Cisplatin and a synergistic effect with Paclitaxel. The response of A2780 cells to Paclitaxel was potentiated in the presence of Chk1 inhibitor PD407824, but not by Wee1 inhibitor MK1775. Our data demonstrates both CHK1 and WEE1 play a role in mediating resistance of A2780 cells to cisplatin and paclitaxel and suggests inclusion of targeted agents against Chk1 or Wee1 may be effective in the treatment of drug-resistant ovarian cancer.