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An integrative framework combines PRISM drug-response data with transcriptomic, metabolomic, and mutational profiles to define molecular programs linked to broad resistance. Network and patient-cohort analyses identify NFE2L2 as a key regulator, while metabolic reprogramming and stress-survival signaling emerge as conserved drivers. Perturbagen screening and experiments show that compounds such as rosiglitazone can reverse resistance signatures and resensitize cells to chemotherapy.",{"@graph":69,"@context":121},[70,84,104],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/multi-omic-integration-identifies-broad-drug-resistance-mechanisms-and-strategies-to-therapeutically-reprogram-cancer-cells-iscience-article/432350/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":98,"encodingFormat":97,"isAccessibleForFree":99,"interactionStatistic":100},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/multi-omic-integration-identifies-broad-drug-resistance-mechanisms-and-strategies-to-therapeutically-reprogram-cancer-cells-iscience-article/432350.png","ImageObject",300,407,{"name":92,"@type":93},"Mimi","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-29",true,{"@type":101,"interactionType":102,"userInteractionCount":4},"InteractionCounter",{"@type":103},"ViewAction",{"@type":105,"mainEntity":106},"FAQPage",[107,113,117],{"name":108,"@type":109,"acceptedAnswer":110},"What data sources are combined in the study’s integrative framework?","Question",{"text":111,"@type":112},"The framework combines PRISM drug-response data with transcriptomic, metabolomic, and mutational profiles to associate molecular programs with broad drug resistance.","Answer",{"name":114,"@type":109,"acceptedAnswer":115},"Which regulator is identified as central to broad resistance programs?",{"text":116,"@type":112},"NFE2L2 is identified as a key regulatory hub linking upstream mutations to oxidative-stress transcriptional programs.",{"name":118,"@type":109,"acceptedAnswer":119},"How do the authors test strategies to therapeutically reprogram resistant cancer cells?",{"text":120,"@type":112},"Computational perturbagen screening nominates compounds predicted to counteract resistance-related transcriptional signatures, and experimental testing confirms that rosiglitazone can reduce NFE2L2-associated gene expression and resensitize resistant cells to chemotherapy.","https://schema.org",{"og:url":83,"og:type":123,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":125,"canonical":83},"index,follow",{"doc_id":127,"site_id":62},432350,1790659279,{"code":4,"msg":5,"data":130},{"doc_id":127,"user_id":131,"nickname":92,"user_avatar":132,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":133,"file_id":134,"file_url":135,"file_type":136,"file_size":137,"view_count":4,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":138,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":128,"read_time":143},2336477974920,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","iScience Article  \nMulti-omic integration identifies broad drug resistance mechanisms and strategies to therapeutically reprogram cancer cells  \nGraphical abstract  \nHighlights  \nAuthors  \nIan Mersich, Brian S.J. Blagg, Aktar Ali  \nCorrespondence  \n[imersich@nd.edu](imersich@nd.edu) (I.M.),  \n[aali4@nd.edu](aali4@nd.edu) (A.A.)  \nIn brief  \nHealth sciences  \n• Multi-omic integration with drug screening data defines mechanisms of drug resistance  \n• Network modeling identifies NFE2L2 as a key regulator of resistance programs  \n• Altered resistance programs in patients have been shown tobe negatively correlated with survival  \n• Perturbagen screening identifies compounds that reprogram resistance programs  \nMersich et al., 2026, iScience 29, 114293  \nJanuary 16, 2026 © 2025 The Authors. Published by Elsevier Inc.  \n[https://doi.org/10.1016/j.isci.2025.114293](https://doi.org/10.1016/j.isci.2025.114293)  \nll  \niScience  \nll  \nOPEN ACCESS  \nArticle  \nMulti-omic integration identifies broad drug resistance mechanisms and strategies to therapeutically reprogram cancer cells  \nIan Mersich,1,2,3,* Brian S.J. Blagg,1,2,3 and Aktar Ali1,2,3,4,*  \n1Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA  \n2Warren Family Research Center for Drug Discovery and Development, University of Notre Dame, Notre Dame, IN 46556, USA  \n3Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA  \n4Lead contact  \n*Correspondence: [imersich@nd.edu](imersich@nd.edu) (I. M.), [aali4@nd.edu](aali4@nd.edu) (A.A.) [https://doi.org/10.1016/j.isci.2025.114293](https://doi.org/10.1016/j.isci.2025.114293)  \nSUMMARY  \nBroad drug resistance arises from diverse transcriptional, metabolic, and genetic adaptations, yet the unifying features that sustain cross-resistant phenotypes remain unclear. We developed an integrative framework combining PRISM drug-response data with transcriptomic, metabolomic, and mutational profiles to define the molecular programs associated with broad resistance and to nominate compounds capable of reversing them. 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 analyses revealed metabolic reprogramming as a conserved feature of resistance, and patient cohort analyses showed that resistance-associated alterations correlated with shorter progression-free survival. Computational perturbagen screening identified compounds predicted to counteract these transcriptional signatures, converging on regulators of NFE2L2 activity. Experimental testing confirmed that rosiglitazone reduced NFE2L2-associated gene expression and re-sensitized resistant cells to chemotherapy, demonstrating a scalable strategy for rational phenotypic reprogramming.  \nINTRODUCTION  \nDrug resistance remains a central barrier to effective cancer treatment, arising through diverse and often multifactorial mechanisms that allow cancer cells to evade the cytotoxic effects of therapy.1–3 Mechanisms driving resistance include enhanced drug efflux via transporters,4–7 alterations in drug targets,8 dysregulation of apoptosis pathways,9–11 and activation of stress-response signaling networks.12–14 Additionally, cancer stem-like cells, cellular quiescence, epithelial-to-mesenchymal transition, and heterogeneous cell populations have been implicated in mediating broad and persistent resistance phenotypes acro cancer types.15–19 Understanding and overcoming these resistance mechanisms is essential for advancing durable cancer therapies and improving patient outcomes.20 ,21  \nThe continued emergence of new mechanisms of multidrug resistance, including adaptations in metabolic pathways and microenvironmental interactions, further underscores the complexity of drug resistance in cancer and the need for ","cbCaigdAxSbiHwVa","https://ap.wps.com/l/cbCaigdAxSbiHwVa","pdf",5359663,22,"English","# Highlights\n# In brief\n# Summary\n# Introduction","[{\"question\":\"What data sources are combined in the study’s integrative framework?\",\"answer\":\"The framework combines PRISM drug-response data with transcriptomic, metabolomic, and mutational profiles to associate molecular programs with broad drug resistance.\"},{\"question\":\"Which regulator is identified as central to broad resistance programs?\",\"answer\":\"NFE2L2 is identified as a key regulatory hub linking upstream mutations to oxidative-stress transcriptional programs.\"},{\"question\":\"How do the authors test strategies to therapeutically reprogram resistant cancer cells?\",\"answer\":\"Computational perturbagen screening nominates compounds predicted to counteract resistance-related transcriptional signatures, and experimental testing confirms that rosiglitazone can reduce NFE2L2-associated gene expression and resensitize resistant cells to chemotherapy.\"}]","Multi-omic integration identifies broad drug resistance mechanisms and strategies to therapeutically reprogram cancer cells - iScience Article | PDF",55]