Franz, A.; Shen, C.; Coscia, F.; Munroe, K.; Charaoui, L.; Korkut, A.; Mann, M.; Luna, A.; Sander, C.

High-grade serous ovarian cancer (HGSOC) remains the most lethal gynecologic malignancy and novel treatment approaches are needed. Here, we used unbiased quantitative protein mass spectrometry to assess the cellular response profile to drug perturbations in ovarian cancer cells for the rational design of potential combination therapies. Analysis of the perturbation profiles revealed proteins responding across several drug perturbations (called frequently responsive below) as well as drug-specific protein responses. The frequently responsive proteins included proteins that reflected general drug resistance mechanisms such as changes in drug efflux pumps. Network analysis of drug-specific protein responses revealed known and potential novel markers of resistance, which were used to rationalize the design of anti-resistance drug pairs. We experimentally tested the anti-proliferative effects of 12 of the proposed drug combinations in 6 HGSOC cell lines. Drug combinations tested with additive or synergistic effects are plausible candidates for overcoming or preventing resistance to single agents; these include several combinations that were synergistic (with PARPi, MEKi, and SRCi). Additionally, we observed 0.05-0.11 micromolar response to GPX4 inhibitors as single agents in the OVCAR-4 cell line. We propose several drug combinations as potential therapeutic candidates in ovarian cancer, as well as GPX4 inhibitors as single agents.