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

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...

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Published in:	EBioMedicine Vol. 60; p. 102988
Main Authors:	Lui, Goldie Y.L., Shaw, Reid, Schaub, Franz X., Stork, Isabella N., Gurley, Kay E., Bridgwater, Caroline, Diaz, Robert L., Rosati, Rachele, Swan, Hallie A., Ince, Tan A., Harding, Thomas C., Gadi, Vijayakrishna K., Goff, Barbara A., Kemp, Christopher J., Swisher, Elizabeth M., Grandori, Carla
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 01-10-2020 Elsevier
Subjects:	Animals Antineoplastic Agents - pharmacology Cell Line, Tumor Dasatinib Disease Models, Animal Drug combinations Drug Synergism Female Gene Expression Profiling Gene Expression Regulation, Neoplastic - drug effects Humans Navitoclax Ovarian cancer Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Ovarian Neoplasms - metabolism Poly(ADP-ribose) Polymerase Inhibitors Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Protein Kinase Inhibitors - pharmacology Proteins - antagonists & inhibitors Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors Research Paper Rucaparib src-Family Kinases - antagonists & inhibitors Transcriptome Xenograft Model Antitumor Assays Dasatinib Drug combinations Rucaparib Navitoclax Poly(ADP-ribose) Polymerase Inhibitors Ovarian cancer
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA GYLL & RS contributed equally to this study.
ISSN:	2352-3964 2352-3964
DOI:	10.1016/j.ebiom.2020.102988