Abstract
Transcriptional states can provide functional information beyond genomic alterations, but whether states derived from nonmalignant physiological perturbations remain informative in cancer is unclear. We separated global RNA-output suppression from relative transcriptional remodeling induced by dihydrotestosterone in mouse adrenal zona fasciculata cells and derived a cross-sex transcriptional signature. Projection of this signature to human orthologs defined an androgen-suppressed transcriptional state (ASTS) across cancer cell lines. Integration with pharmacogenomic and CRISPR dependency datasets showed that higher ASTS was associated with resistance to EGFR-targeted drugs and reduced EGFR dependency, together with increased dependency on mitochondrial pathways, including mitochondrial translation and respiratory electron transport. These associations were not attributable to a single major cancer lineage and remained evident after adjustment for canonical oncogenic drivers and cell-state covariates. ASTS provides a proof of concept that an endocrine-derived transcriptional state can reveal candidate functional vulnerabilities in an unrelated cancer context.