Multi-omic integration identifies broad drug resistance mechanisms and strategies to therapeutically reprogram cancer cells

Broad drug resistance arises from diverse transcriptional, metabolic, and genetic adaptations, yet the unifying features that sustain cross-resistant phenotypes remain unclear. We developed an integrative framework combining PRISM drug-response data with transcriptomic, metabolomic, and mutational profiles to define the molecular programs associated with broad resistance and to nominate compounds capable of reversing them. Resistant cell lines exhibited coordinated activation of extracellular matrix remodeling, stress-adaptation pathways, and survival signaling, with NFE2L2 emerging as a central regulatory hub linking upstream mutations to oxidative-stress transcriptional programs. Multi-omic analyses revealed metabolic reprogramming as a conserved feature of resistance, and patient cohort analyses showed that resistance-associated alterations correlated with shorter progression-free survival. Computational perturbagen screening identified compounds predicted to counteract these transcriptional signatures, converging on regulators of NFE2L2 activity. Experimental testing confirmed that rosiglitazone reduced NFE2L2-associated gene expression and re-sensitized resistant cells to chemotherapy, demonstrating a scalable strategy for rational phenotypic reprogramming.