Abstract 1175: Systematic profiling of conditional pathway activation as a new class of cancer dependency

Abstract

Abstract The paradigm of cancer dependencies and targeted therapies has been nearly exclusively focused on inhibiting critical pathways or nodes in cancer. However, conditional activation of signaling pathways as a new source of selective cancer vulnerabilities has not been systematically characterized. In this study, we sought to systematically identify context-specific gene activation lethalities in cancer. We performed lineage-specific mutual-exclusivity (ME) analysis using 69,393 cancer patient genomes in cohorts of AACR-GENIE, TCGA, and Foundation One, across 12 cancer lineages, and identified ME mutation pairs within MAPK, PI3K and WNT pathways indicative of evolutionarily negative selection. To functionally test whether mutual exclusive genetic alterations likely create negative selection pressures in cancer, we developed a lentiviral method to achieve simultaneous ectopic ORF expression ~500 barcoded cancer cell lines for large-scale gain-of-function genetic perturbation. Using this technology, we systematically profiled the pan-cancer vulnerability landscape upon activating 10 key pathway nodes, revealing selective activation dependencies associated with specific biomarkers. We validated the anti-tumor effect of PI3K hyperactivation in PIK3CA/PTEN double-mutant endometrial cancer cell lines. Notably, we find that subsets of APC-mutant colorectal cancers retain active destruction complexes. Upon further depletion of APC or direct expression of β-catenin, the resulting WNT pathway hyperactivation impairs the viability of APC-mutant colorectal cancers in in vitro cell lines and organoids and in in vivo tumor models. Together, our study reveals a new class of conditional gene activation dependencies in cancer. Citation Format: Liang Chang, Nancy Y. Jung, Adel Atari, Devishi Kesar, Diego J. Rodriguez, Matthew A. Rees, Melissa Ronan, William R. Sellers. Systematic profiling of conditional pathway activation as a new class of cancer dependency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1175.