The recent exciting results using primary PARP inhibitor maintenance after upfront treatment for advanced ovarian cancer in BRCA1/2 mutation carriers highlight the importance of identifying druggable vulnerabilities in this disease. The fact that not all ovarian cancer patients will benefit from PARP inhibitors or experience durable responses, places great emphasis on the need to identify additional therapies. Re-purposing existing FDA-approved drugs offers an opportunity to accelerate progress in this area. Statins are drugs primarily prescribed for hypercholesterolemia and have been intensely researched for decades. Some of this work has demonstrated, through epidemiologic approaches and limited experimental studies, that statins have anticancer properties. We hypothesized that statins can be repositioned as part of a therapeutic regimen for HGSOC. Here, we demonstrate that certain ovarian cancer cell lines are exquisitely sensitive to treatment with statins. Our ongoing studies reveal that HGSOC cells that are sensitive to stain treatment manifest an amplification of chromosome 1q21. Within this genomic region are the S100 proteins, previously identified as potential biomarkers in several cancer types, as well as the anti-apoptotic protein MCL1. We performed a Reverse Phase Protein Array (RPPA) analysis on higher dose/short exposure, and low dose/longer exposure statin-treated cells. In both conditions, MCL1 levels were altered in statin-sensitive cell lines, while there was no such change in non-sensitive lines. After identifying MCL1 as a potential marker of response, Western blot analysis demonstrated a dose-dependent decrease in protein level of MCL1 with increasing statin concentration. Additionally, a short pro-apoptotic splice variant of MCL1 was produced upon statin treatment, but only in the sensitive lines. Mechanistically, we find that phospho-YAP (inactive) is upregulated after statin treatment. This data corroborated previous research that suggested that multiple different statins decrease nuclear YAP. Given its role as an oncogene, the apparent ability of statins to deactivate YAP and downregulate MCL1 steers statins in a promising direction for their repositioning for future therapeutic use.

Citation Format: Paul T. Kroeger, Ronny Drapkin. Evaluating the potential to repurpose statins for ovarian cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5288.