{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T08:26:53Z","timestamp":1787041613693,"version":"build-2736575974"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018990","name":"Alfaisal University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100018990","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioinform."],"abstract":"<jats:p>\n                    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 &amp;lt;0.001, |log\n                    <jats:sub>2<\/jats:sub>\n                    FC| &amp;gt;= 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\u20133 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\u2019s 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.\n                  <\/jats:p>","DOI":"10.3389\/fbinf.2026.1882238","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T07:59:48Z","timestamp":1787039988000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A recurrently perturbed 12-gene program marks drug-tolerant persister states across cancer types"],"prefix":"10.3389","volume":"6","author":[{"given":"Itika","family":"Arora","sequence":"first","affiliation":[{"name":"College of Medicine, Alfaisal University","place":["Riyadh, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed Mohammed","family":"Adam","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, King Abdulaziz University","place":["Jeddah, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdullah O.","family":"Aljaylani","sequence":"additional","affiliation":[{"name":"Research Center, King Faisal Specialist Hospital and Research Center","place":["Jeddah, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jumana Z.","family":"Alzuhayri","sequence":"additional","affiliation":[{"name":"Research Center, King Faisal Specialist Hospital and Research Center","place":["Jeddah, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ehab M. 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