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KRAS-mutant pancreatic and lung cancer cells enter a reversible drug-tolerant state during KRAS inhibition, showing proliferative arrest and extensive metabolic adaptation. Integrated proteomic and metabolomic analyses identify lysosome-linked remodeling and broad metabolic reprogramming. Dual blockade of glutamine metabolism and lysosome-associated processes selectively compromises drug-tolerant cell viability, rescued by α-ketoglutarate and supported by redox-balance effects.",{"@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/dual-targeting-of-glutamine-metabolism-and-lysosomal-function-in-eliminating-drug-tolerant-kras-mutant-cancer-cells-article/357860/",{"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/dual-targeting-of-glutamine-metabolism-and-lysosomal-function-in-eliminating-drug-tolerant-kras-mutant-cancer-cells-article/357860.png","ImageObject",300,407,{"name":92,"@type":93},"nayy☆","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-26","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What limits durable responses to KRAS inhibitors?","Question",{"text":112,"@type":113},"Drug-tolerant persister cells survive initial therapy without classic resistance, enabling relapse.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What happens to KRAS-mutant cells during KRAS inhibition?",{"text":117,"@type":113},"They enter a reversible drug-tolerant state characterized by proliferative arrest and extensive metabolic adaptation.",{"name":119,"@type":110,"acceptedAnswer":120},"How does dual targeting affect drug-tolerant KRAS-mutant cells?",{"text":121,"@type":113},"Simultaneously blocking glutamine metabolism and lysosome-associated processes selectively compromises drug-tolerant cell viability under KRAS inhibition.","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},357860,1790634889,{"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":34,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":36},962090893153,"https://ap-avatar.wpscdn.com/davatar_9964176cb1d06d4a9deccf72a44ae3dc","communications biology Article  \n\n| A Nature Portfolio journal |  | |\n| --- | --- | --- |\n| [https://doi.org/10.1038/s42003-026-10374-x](https://doi.org/10.1038/s42003-026-10374-x) |  |  |\n| Dual targeting of glutamine metabolism and lysosomal function in eliminating drug-tolerant KRAS-mutant cancer cells\u003Cbr> Check for updates |  |  |\n| Hiroki Furukawa1, Keitaro Umezawa 2, Yuchen Sun3, Hinata Chiba1, Marin Kubonishi1, Hayato Naito1, Yuri Miura2, Kousei Ito1 & Shigeki Aoki 1  |  |  |\n| KRAS inhibitors are reshaping the cancer-treatment landscape; however, durable responses remain limited by drug-tolerant persister cells that survive initial therapy and drive relapse. We show that KRAS-mutant pancreatic and lung cancer cells enter a reversible drug-tolerant (TR) state upon KRAS inhibition, marked by proliferative arrest and extensive metabolic adaptation. Integrated proteomicand metabolomic analyses reveal lysosome-linked remodeling and relatively broad metabolic reprogramming in TR cells. Dual blockade of glutamine metabolism and lysosome-associated processes selectively compromises TR-cell viability under KRAS inhibition, which is rescued by α -ketoglutarate(α-KG) . N-acetyl-L-cysteine phenocopies the rescue, andα-KG supplementation lowers intracellular reactive oxygen species levels, supporting a model in whichα-KG acts predominantly asa redox-supportive metabolite rather than a Tricarboxylic Acid Cycle intermediate, in the TR state, with lysosome-associated processes contributing to redox balance. These findings define drug-tolerant redox vulnerability and provide a rationale for co-targeting glutamine metabolism and lysosomeassociated processes during KRAS inhibitor therapy. |  |  |\n| Recent advances in molecular oncology have fundamentally reshaped the therapeutic landscape of cancer1,2. Targeted therapies directed at oncogenicdriver mutations have catalyzed a paradigm shift from broadly cytotoxic regimens to precision medicine, allowing enhanced specificity and delivering markedly improved clinical outcomes2–4. Inhibitors targeting actionable alterations, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), have demonstrated profound clinical efficacy across multiple malignancies, including non-small cell lung cancer (NSCLC), melanoma, and hematologic cancers5–8. Comprehensive genomic profiling has substantially accelerated the discovery of oncogenic drivers, paving the way for developing personalized therapeutic strategies3,9, 10. However, the emergence of drug resistance persists as a formidable and near-universal challenge4, 11. Despite high initial response rates, most patients eventually experience relapse4, 11. This often-transient efficacy is frequently driven by secondary genetic alterations, rewiring of adaptive signaling, or persistence of rare drug-tolerant cell subpopulations11, 12. Although initially undetectable, these cells form the reservoir from which resistance emerges13, 14. Therfore, understanding the mechanisms underlying their survival remains a critical frontier in oncology13, 15. | Oncogenic KRAS is a highly frequently mutated driver in human cancers and has recently become a tractable therapeutic target16, 17. Activating KRAS mutations, most notably G12C inNSCLC and G12D orG12Vin pancreatic ductal adenocarcinoma (PDAC), lead to constitutive activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide-3-kinase signaling pathways, thereby driving tumor aggressiveness16, 17. This progress has been enabled by breakthroughs in designing covalent and non-covalent inhibitors16, 18. Selective inhibitors, such as sotorasib and adagrasib, have demonstrated clinical efficacy, particularly inKRASG12C-mutant NSCLC19,20. However, treatment responses are typically short-lived, with resistance arising via secondary KRAS mutations, pathway reactivation, or adaptive cellular states21,22. These challenges highlight th","cbCaibKvXzQXSBdT","https://ap.wps.com/l/cbCaibKvXzQXSBdT","pdf",5537042,16,"English","# Abstract\n## KRAS inhibitor responses and drug-tolerant states\n## Lysosome-linked remodeling and metabolic adaptation\n## Dual blockade of glutamine metabolism and lysosome-associated processes\n## α-Ketoglutarate rescue and redox-balance model","[{\"question\":\"What limits durable responses to KRAS inhibitors?\",\"answer\":\"Drug-tolerant persister cells survive initial therapy without classic resistance, enabling relapse.\"},{\"question\":\"What happens to KRAS-mutant cells during KRAS inhibition?\",\"answer\":\"They enter a reversible drug-tolerant state characterized by proliferative arrest and extensive metabolic adaptation.\"},{\"question\":\"How does dual targeting affect drug-tolerant KRAS-mutant cells?\",\"answer\":\"Simultaneously blocking glutamine metabolism and lysosome-associated processes selectively compromises drug-tolerant cell viability under KRAS inhibition.\"}]","Dual targeting of glutamine metabolism and lysosomal function in eliminating drug-tolerant KRAS-mutant cancer cells - Article | PDF",1790132100]