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Ref Type Journal Article
PMID (32927276)
Authors Lui GYL, Shaw R, Schaub FX, Stork IN, Gurley KE, Bridgwater C, Diaz RL, Rosati R, Swan HA, Ince TA, Harding TC, Gadi VK, Goff BA, Kemp CJ, Swisher EM, Grandori C
Title BET, SRC, and BCL2 family inhibitors are synergistic drug combinations with PARP inhibitors in ovarian cancer.
Journal EBioMedicine
Vol 60
Issue
Date 2020 Oct
URL
Abstract Text Homologous recombination deficiencies (HRD) are present in approximately half of epithelial ovarian cancers, for which PARP inhibitors (PARPi) are becoming a preferred treatment option. However, a considerable proportion of these carcinomas acquire resistance or harbour de novo resistance, posing a significant challenge to treatment.To identify new combinatorial therapeutics to overcome resistance to PARPi, we employed high-throughput conditional RNAi and drug screening of patient-derived ovarian cancer cells. To prioritise clinically relevant drug combinations, we integrated empirical validation with analysis of The Cancer Genome Atlas (TCGA) and Genomics of Drug Sensitivity in Cancer (GDSC) datasets to nominate candidate targets and drugs, reaching three main findings.Firstly, we found that the PARPi rucaparib enhanced the effect of BET inhibitors (CPI-203 & CPI-0610) irrespective of clinical subtype or HRD status. Additional drug combination screens identified that dasatinib, a non-receptor tyrosine kinase inhibitor, augmented the effects of rucaparib and BET inhibitors, proposing a potential broadly applicable triple-drug combination for high-grade serous and clear cell ovarian carcinomas. Secondly, rucaparib synergised with the BCL2 family inhibitor navitoclax, with preferential activity in ovarian carcinomas that harbour alterations in BRCA1/2, BARD1, or MSH2/6. Thirdly, we identified potentially antagonistic drug combinations between the PARPi rucaparib and vinca alkaloids, anthracyclines, and antimetabolites, cautioning their use in the clinic.These findings propose therapeutic strategies to address PARP inhibitor resistance using agents that are already approved or are in clinical development, with the potential for rapid translation to benefit a broad population of ovarian cancer patients.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown ovarian cancer not applicable Navitoclax + Rucaparib Preclinical - Cell culture Actionable In a preclinical study, the combination of Rubraca (rucaparib) and Navitoclax (ABT-263) resulted in a synergistic effect in ovarian cancer cell lines and patient-derived ovarian cancer cells in culture, and led to increased PARP cleavage compared to treatment with Navitoclax (ABT-263) alone (PMID: 32927276). 32927276
Unknown unknown ovarian cancer not applicable CPI-0610 + Dasatinib + Rucaparib Preclinical - Cell culture Actionable In a preclinical study, the combination treatment of Sprycel (dasatinb), CPI-0610, and Rubraca (rucaparib) resulted in a synergistic effect, demonstrating greater inhibition of colony formation and higher levels of PARP cleavage in ovarian cancer cells in culture compared to double therapy combination treatments (PMID: 32927276). 32927276
Unknown unknown ovarian cancer not applicable CPI-0610 + Dasatinib Preclinical - Cell culture Actionable In a preclinical study, the combination treatment of Sprycel (dasatinb) and CPI-0610 resulted in a synergistic effect, demonstrating greater inhibition of colony formation in ovarian cancer cells in culture compared to either therapy alone (PMID: 32927276). 32927276
Unknown unknown ovarian cancer not applicable Dasatinib + Rucaparib Preclinical - Cell culture Actionable In a preclinical study, the combination treatment of Sprycel (dasatinb) and Rubraca (rucaparib) resulted in a synergistic effect, demonstrating inhibition of colony formation in ovarian cancer cells in culture (PMID: 32927276). 32927276
Unknown unknown ovarian cancer not applicable CPI-0610 + Rucaparib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination treatment of Rubraca (rucaparib) and CPI-0610 resulted in a synergistic effect, demonstrating greater inhibition of cell growth and colony formation in cultured ovarian cancer cells and a 58% decrease in tumor weight in cell line xenograft models (PMID: 32927276). 32927276
Unknown unknown ovarian cancer not applicable Molibresib + Rucaparib Preclinical - Cell culture Actionable In a preclinical study, the combination of Molibresib (GSK525762) and Rubraca (rucaparib) resulted in a synergistic effect, demonstrating greater growth inhibition of ovarian cancer cells in culture compared to Molibresib (GSK525762) treatment alone (PMID: 32927276). 32927276
Unknown unknown ovarian cancer not applicable CPI-203 + Rucaparib Preclinical - Cell culture Actionable In a preclinical study, the combination of CPI-203 and Rubraca (rucaparib) resulted in a synergistic effect, demonstrating greater growth inhibition of ovarian cancer cells in culture compared to CPI-203 treatment alone (PMID: 32927276). 32927276
Unknown unknown ovarian cancer no benefit Rucaparib + Venetoclax Preclinical - Cell culture Actionable In a preclinical study, ovarian cancer cells did not respond to the combination treatment of Rubraca (rucaparib) and Venclexta (venetoclax) in culture (PMID: 32927276). 32927276
Unknown unknown ovarian cancer not applicable Birabresib + Rucaparib Preclinical - Cell culture Actionable In a preclinical study, the combination of Birabresib (OTX015) and Rubraca (rucaparib) resulted in a synergistic effect, demonstrating greater growth inhibition of ovarian cancer cells in culture compared to Birabresib (OTX015) treatment alone (PMID: 32927276). 32927276
Unknown unknown ovarian cancer not applicable JQ1 + Rucaparib Preclinical - Cell culture Actionable In a preclinical study, the combination of JQ1 and Rubraca (rucaparib) resulted in a synergistic effect, demonstrating greater growth inhibition of ovarian cancer cells in culture compared to JQ1 treatment alone (PMID: 32927276). 32927276