Mechanism-aware inference of response to targeted cancer therapies

Targeted therapies like small-molecule inhibitors often work by blocking proteins that cancer cells rely on for survival. Omics based modeling of drug sensitivity alone lack mechanistic grounding. We propose FORGE (Factorization Of Response and Gene Essentiality) a simple yet powerful joint matrix factorization framework that co-models drug response and target gene essentiality, enabling the stratification of promising treatment groups for targeted therapy consideration. FORGE also provides Benefit Score -- a predictive score that estimates treatment efficacy from basal gene expression profiles. We validated the predictive performance of FORGE across multiple targeted therapies, including Erlotinib (EGFR inhibitor) and Daporinad (NAMPT inhibitor). Our meta-analysis of large scale in-vitro studies underscores FORGEs ability to identify common determinants of drug vulnerabilities and target gene essentiality. Such convergences were not observed when treatment vulnerabilities and gene essentialities were modeled independently. We also demonstrated the universality of Erlotinib Benefit Scores by transferring transformations learned from high-throughput drug response studies across other published datasets, including the TAHOE-100M single-cell perturbation atlas and patient-derived xenograft studies. FORGE successfully identified key regulators within the molecular pathways targeted by these therapies, reinforcing its potential for mechanistically grounded treatment stratification.