BET, SRC, and BCL2 family inhibitors are synergistic drug combinations with PARP inhibitors in ovarian cancer.

Autor:	Lui GYL; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Electronic address: glui@fredhutch.org., Shaw R; SEngine Precision Medicine, Seattle, WA, USA; Cure First, Seattle, WA, USA., Schaub FX; SEngine Precision Medicine, Seattle, WA, USA; Cure First, Seattle, WA, USA., Stork IN; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Gurley KE; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Bridgwater C; SEngine Precision Medicine, Seattle, WA, USA., Diaz RL; SEngine Precision Medicine, Seattle, WA, USA., Rosati R; SEngine Precision Medicine, Seattle, WA, USA; Cure First, Seattle, WA, USA., Swan HA; SEngine Precision Medicine, Seattle, WA, USA., Ince TA; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA & New York Presbyterian-Brooklyn Methodist Hospital, Brooklyn, NY, USA., Harding TC; Clovis Oncology, Boulder, CO, USA., Gadi VK; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Goff BA; Department of Obstetrics & Gynecology, University of Washington, Seattle, WA, USA., Kemp CJ; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Swisher EM; Department of Obstetrics & Gynecology, University of Washington, Seattle, WA, USA., Grandori C; SEngine Precision Medicine, Seattle, WA, USA; Cure First, Seattle, WA, USA. Electronic address: cgrandori@senginemedicine.com.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2020 Oct; Vol. 60, pp. 102988. Date of Electronic Publication: 2020 Sep 11.
DOI:	10.1016/j.ebiom.2020.102988
Abstrakt:	Background: 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. Methods: 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. 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. Interpretation: 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. Competing Interests: Declaration of Competing Interest RS, FXS, CB, RLD, RR, HAS, CG were employees of SEngine Precision Medicine during this study. FXS holds stock options in SEngine Precision Medicine. VKG, CJK, CG are cofounders of and have equity positions in SEngine Precision Medicine. TAI holds patents related to Ovarian Carcinoma Modified Ince (OCMI) medium formulation (#20190071634, #20160319239, #20140170693) licensed to US Biological/GLG, and has received grants from US Biological/GLG outside the submitted work. TCH is an employee and stockholder of Clovis Oncology, a company involved in the clinical development of PARP inhibitors. The remaining authors declare no competing interests with relevance to this study. (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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