A high-throughput approach to identify BRCA1-downregulating compounds to enhance PARP inhibitor sensitivity.

Autor:	Sellars E; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.; Women's College Research Institute, Women's College Hospital, Toronto, ON M5S 1B2, Canada., Savguira M; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada., Wu J; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada., Cancelliere S; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada., Jen M; Lunenfeld-Tanenbaum Research Institute, Network Biology Collaborative Centre, High-Throughput Screening, Mt. Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada., Krishnan R; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Hakem A; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Barsyte-Lovejoy D; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada., Hakem R; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada., Narod SA; Women's College Research Institute, Women's College Hospital, Toronto, ON M5S 1B2, Canada.; Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada., Kotsopoulos J; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.; Women's College Research Institute, Women's College Hospital, Toronto, ON M5S 1B2, Canada.; Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada., Salmena L; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.; Women's College Research Institute, Women's College Hospital, Toronto, ON M5S 1B2, Canada.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2024 Jun 04; Vol. 27 (7), pp. 110180. Date of Electronic Publication: 2024 Jun 04 (Print Publication: 2024).
DOI:	10.1016/j.isci.2024.110180
Abstrakt:	PARP inhibitors (PARPi) are efficacious in BRCA1 -null tumors; however, their utility is limited in tumors with functional BRCA1. We hypothesized that pharmacologically reducing BRCA1 protein levels could enhance PARPi effectiveness in BRCA1 wild-type tumors. To identify BRCA1 downregulating agents, we generated reporter cell lines using CRISPR-mediated editing to tag endogenous BRCA1 protein with HiBiT. These reporter lines enable the sensitive measurement of BRCA1 protein levels by luminescence. Validated reporter cells were used in a pilot screen of epigenetic-modifying probes and a larger screen of more than 6,000 compounds. We identified 7 compounds that could downregulate BRCA1-HiBiT expression and synergize with olaparib. Three compounds, N-acetyl-N-acetoxy chlorobenzenesulfonamide (NANAC), A-443654, and CHIR-124, were validated to reduce BRCA1 protein levels and sensitize breast cancer cells to the toxic effects of olaparib. These results suggest that BRCA1-HiBiT reporter cells hold promise in developing agents to improve the clinical utility of PARPi. Competing Interests: The authors have no competing interests to disclose. (© 2024 The Author(s).)
Databáze:	MEDLINE
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