Systematic profiling of conditional pathway activation identifies context-dependent synthetic lethalities.

Publication Type	Academic Article
Authors	Chang L, Jung N, Atari A, Rodriguez D, Kesar D, Song T, Rees M, Ronan M, Li R, Ruiz P, Chaturantabut S, Ito T, van Tienen L, Tseng Y, Roth J, Sellers W
Journal	Nat Genet
Volume	55
Issue	10
Pagination	1709-1720
Date Published	09/25/2023
ISSN	1546-1718
Keywords	Colorectal Neoplasms
Abstract	The paradigm of cancer-targeted therapies has focused largely on inhibition of critical pathways in cancer. Conversely, conditional activation of signaling pathways as a new source of selective cancer vulnerabilities has not been deeply characterized. In this study, we sought to systematically identify context-specific gene-activation-induced lethalities in cancer. To this end, we developed a method for gain-of-function genetic perturbations simultaneously across ~500 barcoded cancer cell lines. Using this approach, we queried the pan-cancer vulnerability landscape upon activating ten key pathway nodes, revealing selective activation dependencies of MAPK and PI3K pathways associated with specific biomarkers. Notably, we discovered new pathway hyperactivation dependencies in subsets of APC-mutant colorectal cancers where further activation of the WNT pathway by APC knockdown or direct β-catenin overexpression led to robust antitumor effects in xenograft and patient-derived organoid models. Together, this study reveals a new class of conditional gene-activation dependencies in cancer.
DOI	10.1038/s41588-023-01515-7
PubMed ID	37749246