Broad drug resistance in cancer arises through diverse transcriptional, metabolic, and genetic adaptations, yet the shared molecular programs that sustain cross-resistant phenotypes remain incompletely defined. This study integrates PRISM drug-response data with transcriptomic, metabolomic, and mutational profiles to characterize the molecular features associated with broad drug resistance and to identify compounds capable of reversing resistance-associated gene signatures. 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 integration further revealed metabolic reprogramming as a conserved hallmark of resistance, and analyses of clinical cohorts demonstrated that resistance-associated alterations were associated with reduced progression-free survival. Computational perturbagen screening nominated compounds predicted to counteract resistance-associated transcriptional signatures. Experimental validation confirmed that rosiglitazone suppressed NFE2L2-associated gene expression programs and restored chemotherapy sensitivity in resistant models, supporting a scalable framework for rational phenotypic reprogramming. This GEO submission provides raw RNA-seq data generated from compound-treated OE19 cells used to experimentally validate candidate re-sensitization strategies.