Abstract
Abstract KEAP1-mutant non-small cell lung cancer is a high prevalence indication that responds poorly to conventional chemotherapy owing to constitutive activation of NRF2 and its associated drug metabolism target genes. Using an approach to identify compounds that selectively kill cancer cell lines in a biomarker-driven manner, we identify BRD-K19050021 (K1905), a compound displaying strong toxicity in cells expressing CYP4F11 - a cytochrome p450 family member and NRF2 transcriptional target. Using genome-wide pooled CRISPR screens, we show that CYP4F11 activity is necessary and sufficient for response to K1905, and in acquired resistance models developed from multiple cell lines, we show a minor subpopulation of cells mechanistically converge on suppressed CYP4F11 expression to bypass K1905 response. CYP4F11 converts K1905 from a prodrug into a covalent active metabolite that alkylates several cellular targets, triggering all three canonical arms of the unfolded protein response pathway and culminating in cell death. We propose that CYP4F11 and similar metabolic enzyme activities promoted by oncogenic drivers represent a unique opportunity to restrict prodrug activation within tumors, provided that normal tissue expression of such prodrug-converting enzymes do not diminish therapeutic index. Citation Format: Aaron Boudreau, Jennifer Roth, James Rong, Niclas Olsson, Chris Mader, Jordan Byran, Jordan Rossen, Li Wang, Kevin Larpenteur, Amy Goodale, Colin Trepicchio, Samantha Bender, Aviad Tsherniak, Aravind Subramanian, Mustafa Kocak, Federica Piccioni, Josh Bittker, Cong Zhu, Frank Li, Nick Eriksson, Daphne Koller, Fiona McAllister, Todd Golub, Jeff Settleman, Ari Firestone, David Stokoe. An oncogene-linked prodrug strategy in lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B121. doi:10.1158/1535-7163.TARG-19-B121
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