High-throughput drug screening identifies EGFR/MAPK pathway targeting sensitivities in organoid models of ovarian carcinosarcoma.

BACKGROUND: Ovarian carcinosarcoma (OCS) is a rare and aggressive tumour type with limited treatment options. Standard therapy includes platinum agents, but responses are poor. OCS highly express mesenchymal markers, such as N-MYC and HMGA2. The microtubule-targeting drug eribulin can reduce expression of N-MYC and HMGA2 in OCS PDX models and functionally reverse EMT in OCS cell lines. METHODS: In this study, we carried out drug screens in the presence of cisplatin or eribulin to identify synergistic combinations. We validated top combinations in our unique OCS cell line, organoid and PDX models. RESULTS: The most effective combination treatments in OCS organoid models involved eribulin, whereas cisplatin-based combination therapies were more effective in high-grade serous ovarian cancer (HGSOC) models. Eribulin combined with either an EGFR inhibitor (erlotinib) or a MEK inhibitor (mirdametinib/PD0325901) were the most effective combinations in OCS models, with a synergistic effect being observed in two (out of four) models for each combination. Mechanistically, OCS models appeared to be particularly reliant on EGFR and MAPK signalling in vitro, especially in tumours with TP53 mutation. In vivo, only modest improvements in survival were observed for eribulin plus erlotinib, however, two of the three OCS PDX models tested were found to have drug resistance mechanisms, such as high ABCB1 expression (encoding the multi-drug resistance protein which causes drug efflux) or a KRAS constitutive activation mutation (a known resistance mechanism to EGFR inhibitors). KRAS mutant OCS cell lines and organoids were sensitive to dual targeting of the EGFR/MAPK pathway, with statistically greater synergy observed when eribulin was added as a third drug. CONCLUSIONS: OCS is the most aggressive, drug-resistant gynaecological malignancy and eribulin-based combination therapies, particularly triple combination therapies, have the potential to improve patient outcomes.