Ovarian cancer BROCA sequencing

Background: Homologous recombination deficiencies (HRD) are present inapproximately half of epithelial ovarian cancers, for which PARP inhibitors (PARPi) arebecoming a preferred treatment option. However, a considerable proportion of thesecarcinomas acquire resistance or harbour de novo resistance, posing a significantchallenge to treatment.Methods: To identify new combinatorial therapeutics to overcome resistance to PARPi,we employed high-throughput conditional RNAi and drug screening of patient-derivedovarian cancer cells. To prioritise clinically relevant drug combinations, we queried TheCancer Genome Atlas (TCGA) and Genomics of Drug Sensitivity in Cancer (GDSC)project with the candidate targets and their respective drugs to reach three mainfindings.Findings: Firstly, we found that rucaparib enhanced the effect of BET inhibitors(CPI-203 & CPI-0610) irrespective of clinical subtype or HRD status. Dasatinib, a non-receptor tyrosine kinase inhibitor, augmented the synergy of rucaparib and BETinhibitors, proposing a potential broadly applicable triple-drug combination for high-gradeserous and clear cell ovarian carcinomas. Secondly, rucaparib synergised with the BCL2family inhibitor navitoclax, with preferential activity in ovarian carcinomas that harbouralterations in BRCA1/2, BARD1, or MSH2/6. Thirdly, we identified potentiallyantagonistic drug combinations between the PARPi rucaparib and vinca alkaloids,anthracyclines, and antimetabolites, cautioning their use in the clinic.Interpretation: These findings illuminate new insights into PARP inhibitor resistanceand propose novel therapeutic combinations that could benefit broader populations ofovarian cancer patients.