Background: Low Grade Serous Ovarian Carcinoma (LGSOC) is a molecularly distinct subtype of ovarian cancer that is synonymous with chemotherapy resistance. The rarity of LGSOC has impeded global research efforts into novel treatments which has subsequently led to survival inequities. As such we undertook the largest LGSOC high-throughput sigle agent and synergistic drug screening effort to identify novel treatment strategies.

Methods: Twelve patient-derived LGSOC cell lines representing the molecular diversity of thr disease were screened in 2D with 3486 single agents from FDA approved/clinically tested (n=2322), kinase (n=430) and epigenetic (n=684) drug libraries. Each cell line was treated for 72hrs (0.1,1 & 10µM) with cell viability normalized to DMSO treated controls and IOSE-532 cells (normal ovarian surface epithelium).

Results: Three Phase 2/FDA approved compounds (MAPK and JAK/STAT inhibitors) induced cytotoxicity across all LGSOC cell lines (0.1µM) regardless of molecular subtype (Z-score <-2) with no effect observed in IOSE-532 control cells. In addition, 111 compounds were also identified to be effective in ≥50% cell lines (LGSOC Z-score <-2 and IOSE-532 Z-score >-2) or enriched within specific molecular subtypes. Compounds have now been tested in synergy with each other along with standard of care treatment, where we have identified a number of lead combination.

Conclusions: LGSOC are addicted to a limited number of unique ‘driver’ genes, copy number changes and cancer signalling pathways. We have identified several single and combination compounds effective for all LGSOCs and within specific molecular subtypes that will pave the way for new treatment strategies which we will validate using preclinical models.