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It highlights allele-specific covalent approaches for KRAS-G12C, including FDA-approved sotorasib, and surveys clinical-stage strategies such as pan-RAS inhibitors, RAS-effector pathway inhibitors, and immune checkpoint inhibitor combinations.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/small-molecular-inhibitors-for-kras-mutant-cancers/378166/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/small-molecular-inhibitors-for-kras-mutant-cancers/378166.png","ImageObject",300,407,{"name":42,"@type":43},"Aditya","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-31","2026-09-24",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",8,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"Why are KRAS and other RAS mutations considered difficult targets in cancer therapy?","Question",{"text":63,"@type":64},"RAS mutations lock RAS proteins in a constitutively active state, driving downstream pathways such as MAPK and PI3K. Historically, developing effective RAS-inhibiting agents has been unsuccessful for a long time.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What has enabled recent progress against KRAS-mutant cancers?",{"text":68,"@type":64},"Discovery of a new binding site beneath the effector binding switch-II region in RAS supported allele-specific covalent inhibitors targeting KRAS-G12C, which showed promising efficacy in clinical trials.",{"name":70,"@type":61,"acceptedAnswer":71},"What treatment options are emphasized in this review for KRAS-mutant cancers?",{"text":72,"@type":64},"The review covers progress in small-molecule inhibitors, including direct KRAS inhibitors, pan-RAS inhibitors, inhibitors of RAS effector signaling, and immune checkpoint inhibitor strategies combined with RAS inhibitors.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},378166,1790405940,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,114,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":108,"slug":109},7,40,"healthcare",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":111,"show_sort_weight":112,"slug":113},"Research & Report",30,"research-report",{"id":115,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},9,"Religion & Spirituality",20,"religion-spirituality",{"id":117,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":117,"slug":121},"World Cup","world-cup",{"id":123,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":123,"slug":125},10,"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":107,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":139,"language":140,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":12,"update_tm":144,"read_time":112},962085564549,"https://ap-avatar.wpscdn.com/davatar_085a072bc5b1113ac321206ff7593b45","TYPE Review  \nPUBLISHED 18 August 2023  \nDOI 10.3389/fimmu.2023.1223433  \nOPEN ACCESS  \nEDITED BYEsra Akbay,  \nUniversity of Texas Southwestern Medical Center, United States  \nREVIEWED BY Yufei Luo,  \nHunan University, China Samantha Messina, Roma Tre University, Italy  \n*CORRESPONDENCE Ding Li  \n [ld_sunshinev@163.com](ld_sunshinev@163.com)  \nRECEIVED 16 May 2023  \nACCEPTED 31 July 2023  \nPUBLISHED 18 August 2023  \nCITATION  \nWu X, Song W, Cheng C, Liu Z, Li X, Cui Y, Gao Y and Li D (2023) Small molecular inhibitors for KRAS-mutant cancers.  \nFront. Immunol. 14:1223433 .  \ndoi: 10.3389/fimmu.2023.1223433  \nCOPYRIGHT  \n© 2023 Wu, Song, Cheng, Liu, Li, Cui, Gao and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.  \nSmall molecular inhibitors for KRAS-mutant cancers  \nXuan Wu 1,2, Wenping Song 3,4,5, Cheng Cheng 1, Ziyang Liu 2, Xiang Li 1, Yu Cui 1, Yao Gao 1 and Ding Li 3,4,5*  \n1 Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China, 2Academy of Medical Science, Zhengzhou University, Zhengzhou, China, 3 Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China, 4 Henan Engineering Research Center for Tumor Precision Medicine and Comprehensive Evaluation, Henan Cancer Hospital, Zhengzhou, China,  \n5 Henan Provincial Key Laboratory of Anticancer Drug Research, Henan Cancer Hospital, Zhengzhou, China  \nThree rat sarcoma (RAS) gene isoforms, KRAS, NRAS, and HRAS, constitute the most mutated family of small GTPases in cancer. While the development of targeted immunotherapies has led to a substantial improvement in the overall survival of patients with non-KRAS-mutant cancer, patients with RAS-mutant cancers have an overall poorer prognosis owing to the high aggressiveness of RAS-mutant tumors. KRAS mutations are strongly implicated in lung, pancreatic, and colorectal cancers. However, RAS mutations exhibit diverse patterns of isoforms, substitutions, and positions in different types of cancers. Despite being considered “undruggable”, recent advances in the use of allele-specific covalent inhibitors against the most common mutant form of RAS in non-smallcell lung cancer have led to the development of effective pharmacological interventions against RAS-mutant cancer . Sotorasib (AMG510) has been approved by the FDA as a second-line treatment for patients with KRAS-G12C mutant NSCLC who have received at least one prior systemic therapy. Other KRAS inhibitors are on the way to block KRAS-mutant cancers. In this review, we summarize the progress and promise of small-molecule inhibitors in clinical trials, including direct inhibitors of KRAS, pan-RAS inhibitors, inhibitors of RAS effector signaling, and immune checkpoint inhibitors or combinations with RAS inhibitors, to improve the prognosis of tumors with RAS mutations.  \nKEYWORDS  \nRAS mutation, different isoform, RAS inhibitor, immunotherapy, combination strategy  \n1 Introduction  \nRat sarcoma (RAS) genes have been recognized as the major oncogenes undergoing mutation for several decades (1, 2) . Among the three isoforms (KRAS, NRAS, and HRAS), Kirsten rat sarcoma viral oncogene homolog (KRAS) is the common oncogene in a large percentage of cancers, including pancreatic cancer, non-small cell lung cancer (NSCLC), and colorectal cancer (3–6) . Mutations in RAS lead to the dysfunction of its small GTPase activity, preventing it from properly breaking down GTP. The molecule remains in a  \nFrontiers in Immunology 01 [frontiersin.org](frontiersin.org)  ","cbCaijoNiVCj1NRA","https://ap.wps.com/l/cbCaijoNiVCj1NRA","pdf",1222775,12,"English","# Introduction\n# RAS mutations in human cancers","[{\"question\":\"Why are KRAS and other RAS mutations considered difficult targets in cancer therapy?\",\"answer\":\"RAS mutations lock RAS proteins in a constitutively active state, driving downstream pathways such as MAPK and PI3K. Historically, developing effective RAS-inhibiting agents has been unsuccessful for a long time.\"},{\"question\":\"What has enabled recent progress against KRAS-mutant cancers?\",\"answer\":\"Discovery of a new binding site beneath the effector binding switch-II region in RAS supported allele-specific covalent inhibitors targeting KRAS-G12C, which showed promising efficacy in clinical trials.\"},{\"question\":\"What treatment options are emphasized in this review for KRAS-mutant cancers?\",\"answer\":\"The review covers progress in small-molecule inhibitors, including direct KRAS inhibitors, pan-RAS inhibitors, inhibitors of RAS effector signaling, and immune checkpoint inhibitor strategies combined with RAS inhibitors.\"}]","Small molecular inhibitors for KRAS-mutant cancers | PDF",1790228751]