Estoppey, David, Schutzius, Gabi, Kolter, Christian, Salathe, Adrian, Wunderlin, Tiffany, Meyer, Amandine, Hoepfner, Dominic and Bouwmeester, Antonius (2021) CRISPR-Cas9 screen identifies mechanisms of BET bromodomain inhibitor sensitivity including manganese. iScience, 24 (11). p. 103323.

Abstract

BET Bromodomain Inhibitors hold promise as therapeutic agents in inflammation and cancer but clinical studies show adverse side-effects at high, sustained dose. Clinical success requires further mechanistic understanding of inhibition of BET bromodomains and biomarkers to optimize efficacious dosing. To uncover the mechanisms of sensitivity and resistance to BETi, we employed a whole-genome CRISPR-Cas9 proliferation screen using colorectal cancer cells. We identify the mTOR signaling pathway as a key determinant of BETi sensitivity and that two Ca/Mn transporters mediate resistance. This later finding led to the discovery that extracellular manganese regulates sensitivity to BETi and that exposure of cells to BETi dose dependently increases intracellular manganese concentration. Our results describe new molecular pathways mediating BETi action and suggest several potential avenues for biomarker discovery.

Item Type:	Article
Date Deposited:	21 Dec 2021 00:45
Last Modified:	21 Dec 2021 00:45
URI:	https://oak.novartis.com/id/eprint/41441