[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-374847-105":59,"doc-detail-374847-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","adaptive-cancer-therapy-can-non-genetic-factors-become-its-achilles-heel","Adaptive cancer therapy: can non-genetic factors become its achilles heel?","","Adaptive cancer therapy addresses how resistance emerges during standard-of-care chemotherapy delivered at maximum tolerated doses. Instead of aiming for immediate eradication, adaptive therapy manages evolutionary dynamics by preserving a pool of sensitive cells that compete with resistant phenotypes via dose modulation and/or timing, thereby prolonging control. This review examines non-genetic resistance mechanisms—such as protective tumor stroma, epithelial-to-mesenchymal transition, drug efflux pump overexpression, and extracellular vesicle–mediated transfer—that can expand resistant populations and reduce the ability of adaptive strategies to steer tumor evolution toward controllable outcomes.",{"@graph":69,"@context":122},[70,84,105],{"@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":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/adaptive-cancer-therapy-can-non-genetic-factors-become-its-achilles-heel/374847/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/adaptive-cancer-therapy-can-non-genetic-factors-become-its-achilles-heel/374847.png","ImageObject",300,407,{"name":92,"@type":93},"Mary Man","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What problem does adaptive cancer therapy try to solve compared with maximum tolerated dose chemotherapy?","Question",{"text":112,"@type":113},"Maximum tolerated dose chemotherapy can accelerate the elimination of sensitive cells, enabling resistant phenotypes to expand through evolutionary mechanisms. Adaptive therapy instead aims to control tumor evolution by managing resistant dynamics over time.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does adaptive therapy preserve sensitive cells to improve long-term disease control?",{"text":117,"@type":113},"Adaptive therapy maintains a pool of treatment-sensitive cancer cells so they can compete with therapy-resistant cells. It uses dynamic dose modulation and/or timing so fluctuations in sensitive-cell populations limit resistant growth.",{"name":119,"@type":110,"acceptedAnswer":120},"Which non-genetic resistance mechanisms does the review highlight?",{"text":121,"@type":113},"The review discusses non-genetic mechanisms including protective roles of the tumor stroma, epithelial-to-mesenchymal transition, overexpression of drug efflux pumps, and extracellular vesicle–mediated transfer of these resistance-associated factors.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},374847,1790242963,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":34,"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":143,"read_time":144},7421720224475,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","Oncogene [www.nature.com/onc](www.nature.com/onc)  \nREVIEW ARTICLE OPEN   \nAdaptive cancer therapy: can non-genetic factors become its achilles heel?  \nGábor Valcz 1,2 ✉, Robert A. Gatenby 3,4, Beáta Újvári 5, Edit I. Buzás1,6,7 and Béla Molnár2  \n© The Author(s) 2025  \n|  |  |  |\n| --- | --- | --- |\n|  | The recurrence of clinically advanced cancers is an evolutionary consequence of standard-of-care chemotherapies generally administered at maximum tolerated doses to kill as many cancer cells as possible. The inevitable appearance of resistance raises the possibility of shifting treatment goals from complete tumor eradication to long-term disease control. The latter approach is employed by adaptive therapy, which aims to inhibit the evolutionary dynamics governing the spread of resistant tumor phenotypes. Adaptive therapy changes focus from the cancer cells that are responsive to therapy to those that are resistant and ultimately govern outcome. This therapeutic approach retains a pool of sensitive cancer cells to compete with the therapy-resistant ones through dynamic dose modulation and/or timing. Thus, fluctuations of treatment-sensitive cells are used to control the resistant population and prolong tumor control with existing therapy agents. Here, we explore non-genetic mechanisms of resistance, including the protective role of the tumor stroma, the epithelial-to-mesenchymal transition, the overexpression of drug efflux pumps, and the extracellular vesicle-mediated transfer of them. These mechanisms can increase the size of the resistant population at the expense of the sensitive one, reducing the ability of adaptive therapy to force tumor evolution into controllable |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n| cycles. |  |  |\n|  | Oncogene (2025) 44:3999–4005; [https://doi.org/10.1038/s41388-025-03582-y](https://doi.org/10.1038/s41388-025-03582-y) |  |\n|  |  |  |\n\nINTRODUCTION  \nThe diagnosis of cancer is frequently perceived as a fundamental threat to existence, triggering a strong desire to completely and quickly eradicate the disease as a general goal of cancer treatment [1] . This “hit hard and fast” urge is partially satisfied by protocolfixed, systemically administered cytotoxic therapies. These therapies are typically administered at or near the maximum tolerated dose (MTD), often within the shortest possible time (“maximum dose density”), to induce lethal toxicity in as many cancer cells as possible [2] . Although this strategy often results in significant tumor response, these aggressive therapies inevitably select for resistant phenotypes within the large, heterogeneous cancer population leading to treatment failure and tumor progression (intratumoral heterogeneity illustrated in Fig. 1A) [1, 3] . In essence, even the most effective current therapies eventually fail because cancer functions as an independent eco-evolutionary system, capable of adapting to potentially lethal therapeutic interventions by developing and disseminating dynamic, adaptive strategies [3, 4] . Cells that possess the molecular mechanisms necessary for overcoming therapeutic challenges form surviving foci called“minimal residual disease” (MRD), which is usually undetectable by clinical tests [3, 5] . Paradoxically, MTD treatment only worsens the scenario by accelerating the elimination of sensitive cells. So, it can“release” the existing resistant cells from competition-caused suppression resulting in overgrowth of minimal residual disease  \n(Fig. 1B) [6] . Thus, the dominance and rapid expansion of resistance are a consequence of the evolutionary mechanism known as competitive release [1, 7, 8] .  \nWith the recognition of the evolutionary limitations of traditional maximum dose treatments, researchers started focusing on therapies that can steer tumor evolution to provide greater patient benefit [6, 7, 9]. Adaptive therapy (AT) was one of the first attempts at cli","cbCais2bqROPG8MW","https://ap.wps.com/l/cbCais2bqROPG8MW","pdf",1383910,"English","# Introduction\n# Adaptive therapy and evolutionary principles\n## Competitive release and resistance management\n# Non-genetic mechanisms of resistance\n## Tumor stroma protection\n## Epithelial-to-mesenchymal transition\n## Drug efflux pumps\n## Extracellular vesicle–mediated transfer\n# Implications for adaptive therapy","[{\"question\":\"What problem does adaptive cancer therapy try to solve compared with maximum tolerated dose chemotherapy?\",\"answer\":\"Maximum tolerated dose chemotherapy can accelerate the elimination of sensitive cells, enabling resistant phenotypes to expand through evolutionary mechanisms. Adaptive therapy instead aims to control tumor evolution by managing resistant dynamics over time.\"},{\"question\":\"How does adaptive therapy preserve sensitive cells to improve long-term disease control?\",\"answer\":\"Adaptive therapy maintains a pool of treatment-sensitive cancer cells so they can compete with therapy-resistant cells. It uses dynamic dose modulation and/or timing so fluctuations in sensitive-cell populations limit resistant growth.\"},{\"question\":\"Which non-genetic resistance mechanisms does the review highlight?\",\"answer\":\"The review discusses non-genetic mechanisms including protective roles of the tumor stroma, epithelial-to-mesenchymal transition, overexpression of drug efflux pumps, and extracellular vesicle–mediated transfer of these resistance-associated factors.\"}]","Adaptive cancer therapy: can non-genetic factors become its achilles heel? | PDF",1790202564,18]