Multiomic characterization of microsatellite-stable colorectal cancer reveals distinct biology and targetable vulnerabilities.

Microsatellite-stable (MSS) colorectal cancer (CRC) is a molecularly complex and clinically challenging disease subtype, lacking effective targeted therapies. Leveraging multiomic data from ∼2,000 tumor samples (including 316MSS CRCs not previously profiled) representing ∼4,500 molecular profiles and 195,246 single cells/nuclei, we uncover complex biology and therapeutic vulnerabilities. Application of a multiomic-phenomic integrative framework, including iPhenMap (a machine-learning tool), reveals complex molecular programs, including replication stress, right-sided biology, glutaminolysis-driven metabolic reprogramming, and MYC-E2F transcriptional networks governing epigenetic remodeling and perineural invasion. Focusing on RAS-mutant MSS CRC, functional validation in state-of-the-art patient-derived tumoroid and matched xenograft models confirms focal adhesion kinase (FAK), phosphoinositide-dependent kinase (PDK)1/2, and proteasome inhibition as potential therapeutic strategies when combined with mitogen-activated protein kinase (MEK) blockade. This work underscores the power of integrated multiomic profiling and functional modeling to refine potential treatment approaches in MSS CRC patient populations.