A recurrently perturbed 12-gene program marks drug-tolerant persister states across cancer types.

Drug-tolerant persister (DTP) cells survive therapeutic stress through reversible, non-genetic adaptations, driving treatment failure across cancers. Whether a recurrently perturbed program defines the DTP state across cancer types remains poorly characterized. We performed integrated transcriptomic analysis across five GEO RNA-seq datasets representing breast, lung, pancreatic, colorectal, and melanoma DTP models. A stringent 12-gene signature, PanDTP-12, was established from genes meeting differential expression criteria (FDR <0.001, |log2FC| >= 0.8) across four discovery datasets. Module scores showed complete separation between persister and control samples (within-dataset and pooled AUC = 1.0; n = 16), though trivially small per-dataset sample sizes (n = 2-3 per group) preclude interpreting AUC = 1.0 as a stable performance estimate. Sensitivity analysis confirmed that all 12 genes remained recurrent when the fasting-quiescence dataset GSE214537 was excluded. In an independent PC9 NSCLC dataset (GSE255958), PanDTP-12 showed high directional concordance (9/12 genes) and quantitative module-score separation between parental PC9D and day-9 persister PC9O9 samples (AUC = 1.0, Cohen's d = 14.76), though these metrics are based on only 6 samples and should be interpreted with caution. INK128-induced DTP models in MCF-7 and HCT116 cells demonstrated cell-cycle arrest, morphological changes, and RT-qPCR confirmation of PanDTP-12 upregulation (12/12 significant in HCT116; 6/12 in MCF-7). Drug-repurposing analysis identified focused drug-gene interactions among PanDTP-12 members. These findings identify PanDTP-12 as a recurrently perturbed twelve-gene program marking the DTP state across cancer types. The signature offers focused pharmacological hypotheses through druggable members (CLK1, XBP1, and KLF5) and establishes a framework for translational assessment of DTP-directed therapeutics, though larger validation cohorts and functional studies will be needed to confirm clinical utility.