Integrated Genomic Profiling Reveals Mechanisms of Broad Drug Resistance and Opportunities for Phenotypic Reprogramming in Cancer Cells

Broad drug resistance is a major barrier to effective cancer therapy, driven by diverse genetic, transcriptional, and metabolic adaptations across tumor types. Here, we developed an integrative computational framework that leverages PRISM drug sensitivity profiles from DepMap, multi-omic datasets, and perturbagen libraries to systematically characterize and identify strategies to reverse broad resistance in cancer cell lines. We found that resistant lines exhibit transcriptional programs enriched for extracellular matrix remodeling, stress adaptation, and survival signaling, with NFE2L2 emerging as a central regulatory hub linked to upstream mutations and downstream oxidative stress pathways. Integrated metabolomics and transcriptomics highlighted metabolic reprogramming as a hallmark of resistance, while mutation analyses revealed convergence on growth factor and ECM-related pathways. These features were also reflected in patient cohorts, where resistance-associated mutations correlated with reduced progression-free survival across diverse cancer types. Computational perturbagen screening identified candidate compounds predicted to reverse resistance-associated gene expression profiles, converging on actionable targets including NFE2L2, ABCB1, and CYP3A4, with compounds such as brefeldin A and nocodazole predicted to have strong activity in resistant lines. This study establishes a scalable, mechanism-informed framework for rationally identifying and prioritizing compounds to overcome broad drug resistance in cancer, providing a roadmap for targeted re-sensitization strategies.