%0 Journal Article
%T A high-throughput approach to identify BRCA1-downregulating compounds to enhance PARP inhibitor sensitivity.
%A Sellars E
%A Savguira M
%A Wu J
%A Cancelliere S
%A Jen M
%A Krishnan R
%A Hakem A
%A Barsyte-Lovejoy D
%A Hakem R
%A Narod SA
%A Kotsopoulos J
%A Salmena L
%J iScience
%V 27
%N 7
%D 2024 Jul 19
%M 38993666
%F 6.107
%R 10.1016/j.isci.2024.110180
%X 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.