Identifying Vulnerabilities and Novel Drug Candidates in Platinum-Resistant Ovarian Cancer

Ovarian cancer is the fifth leading cause of female, cancer-related death in the United States and the deadliest form of gynecological cancer (Cancer Facts & Figures 2022, 2022). Epithelial ovarian cancer (EOC) accounts for 90% of all diagnosed ovarian cancers, 70% of which are High Grade Serous Ovarian Cancer (HGSOC), with a five-year survival rate less than 25% (Cai et al., 2014; Ediriweera et al., 2019; Iyengar et al., 2018; Lisio et al., 2019; Siwak et al., 2010). Platinum-taxane combination therapy has been the standard of care since its introduction in the 1990s yet, over 70% of HGSOC patients relapse due to platinum resistance (PR) (Kim et al., 2012; Kristedja et al., 2010; Moghbeli, 2021). There is a critical need for alternative therapeutic options for PR HGSOC. Here, we aimed to generate models of PR from HGSOC cell lines intrinsically sensitive to cisplatin and screen them against a panel of 225 small molecule inhibitors. The panel consists of FDA-approved drugs currently being used clinically, drugs in Phase II or III clinical trials, as well as novel-preclinical small molecule kinase inhibitors and tool compounds to identify single agents and/or pathways of interest in combating PR. Aligning with previous research, selective EGFR and PI3K inhibitors elicited significant responses in the PR model compared to the parental cell line. Lastly, the MEK inhibitor, cobimetinib, displayed advantageous responses in the PR model and highlight the MEK pathway to be further investigated in the context of PR HGSOC.