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Despite significant advancements, it remains unclear whether conserved molecular programs underpin therapy resistance across cancer types.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Here, we integrate single-cell RNA sequencing, spatial transcriptomics, regulatory network modeling, transcription factor binding data, and pharmacologic perturbation across multiple cancer types to define a conserved, proliferative chemoresistant tumor state.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Contrary to the prevailing notion that resistance arises from quiescent or EMT-like phenotypes, we find that resistant tumor cells display elevated G2\/M and S-phase activity, enriched expression of E2F and MYC target genes, and activation of DNA repair and PI3K\/AKT signaling pathways. We identify the transcription factor MYC as a central regulator of the resistant state, with progressive activation along the resistance trajectory and focal expression in resistant epithelial niches. A novel MYC target, SRM (Spermidine Synthase), emerges as a conserved effector of resistance, promoting polyamine biosynthesis critical for chromatin stability and metabolic resilience. SRM expression correlates with MYC binding and predicts poor patient survival. Functional validation in cell lines, patient-derived organoids and mouse models demonstrate that pharmacologic inhibition of MYC, SRM, or WNT signalling restores chemotherapy sensitivity, suppresses resistance-associated pathways, and reactivates apoptosis. Spatial and survival analyses confirm the clinical relevance of the MYC\u2013SRM axis, establishing it as a druggable module in treatment-refractory cancers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>To our knowledge, this is the first comprehensive study that redefines chemoresistance as a proliferative, MYC-driven state and uncover SRM as a tractable vulnerability, offering new avenues for therapeutic intervention across diverse epithelial malignancies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-026-01763-2","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T02:45:00Z","timestamp":1789526700000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Uncovering pan-cancer signatures of chemoresistance"],"prefix":"10.1186","volume":"18","author":[{"given":"Mohammed","family":"Inayatullah","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Engin","family":"Demirdizen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachery","family":"Keepers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catarina Mendes","family":"Correia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyyed Morteza","family":"Hashemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaushlendra","family":"Tripathi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Souren","family":"Sadhukhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ishita","family":"Bardhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun","family":"Mahesh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feyruz V.","family":"Rassool","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikkel Green","family":"Terp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hem D.","family":"Shukla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay K.","family":"Tiwari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"1763_CR1","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1038\/nrc3599","volume":"13","author":"C Holohan","year":"2013","unstructured":"Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. 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