Background: Low-grade serous ovarian carcinoma (LGSOC) is a distinct form of ovarian cancer characterized by its inherent resistance to chemotherapy, underscoring the urgent need for new therapeutic options. High-throughput screening using clinically relevant cell-based models offers a promising approach for identifying potential treatments to prioritize for clinical trials.

Methods: We conducted a high-throughput drug screening of 1610 compounds across a panel of 6 LGSOC cell lines (3 with RAS/RAF mutations and 3 with wild-type RAS/RAF) to discover novel therapeutic candidates. Validation included dose-response assessments across 9 LGSOC models and 5 high-grade serous ovarian carcinoma (HGSC) comparator lines.

Results: Of the 1610 compounds tested, 16 were selected for further validation based on their ability to reduce nuclear counts by more than 50% in over half of the cell lines at a concentration of 1000 nM. Eleven compounds passed validation, with four agents showing the most promise: dasatinib (a tyrosine kinase inhibitor), disulfiram (an aldehyde dehydrogenase inhibitor), carfilzomib (a proteasome inhibitor), and romidepsin (a histone deacetylase inhibitor). These compounds were further tested for synergy with the recently approved MEK inhibitor trametinib. Disulfiram exhibited remarkable selectivity for LGSOC compared to HGSC lines (P = 0.003 for IC50 comparison), while dasatinib showed significant synergy with trametinib in multiple LGSOC models (with a maximum synergy score of 46.9). The novel Src family kinase (SFK) inhibitor NXP900 displayed a similar synergy profile to dasatinib, suggesting that SFK inhibition may drive the observed synergy.

Conclusion: Dasatinib and other SFK inhibitors are promising novel treatments for LGSOC, demonstrating synergy with trametinib. Disulfiram also offers a potential treatment strategy that warrants further exploration. KRpep-2d