[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-339742-105":3,"detail-sidebar-cat-0-en-105":73,"doc-detail-339742-en":123},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":66,"head_meta":68,"extra_data":70,"updated_unix":72},105,"en","targeting-krasg12d-mutation-in-non-small-cell-lung-cancer-molecular-mechanisms-and-therapeutic-potential-review-article","Targeting KRASG12D mutation in non-small cell lung cancer - molecular mechanisms and therapeutic potential - review article","","This review article examines how targeting the KRASG12D mutation in non-small cell lung cancer (NSCLC) may be approached, detailing the molecular basis of KRAS-driven signaling and why KRAS has historically been difficult to drug. It contrasts the rapid progress achieved for the KRASG12C subtype with the slower development for KRASG12D, noting the lack of approved KRASG12D-specific therapies. The discussion emphasizes key challenges including resistance mechanisms, optimal combination strategies across treatment modalities, and the clinical efficacy of KRASG12D inhibitors.",{"@graph":14,"@context":65},[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/targeting-krasg12d-mutation-in-non-small-cell-lung-cancer-molecular-mechanisms-and-therapeutic-potential-review-article/339742/",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/targeting-krasg12d-mutation-in-non-small-cell-lung-cancer-molecular-mechanisms-and-therapeutic-potential-review-article/339742.png","ImageObject",300,407,{"name":42,"@type":43},"Liam","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-31","2026-09-21",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",17,{"@type":57,"mainEntity":58},"FAQPage",[59],{"name":60,"@type":61,"acceptedAnswer":62},"What molecular properties of KRAS are relevant to drug development?","Question",{"text":63,"@type":64},"KRAS cycles between active GTP-bound and inactive GDP-bound conformations, and mutated KRAS remains activated, driving downstream signaling that supports tumor formation. The review also notes that developing direct KRAS inhibitors was historically difficult, in part due to nucleotide binding characteristics and lack of suitable regulatory pockets.","Answer","https://schema.org",{"og:url":32,"og:type":67,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":69,"canonical":32},"index,follow",{"doc_id":71,"site_id":7},339742,1790104843,{"code":4,"msg":74,"data":75},"success",[76,80,84,88,93,98,102,107,112,115,119],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":77,"show_sort_weight":78,"slug":79},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":81,"show_sort_weight":82,"slug":83},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Exam",70,"exam",{"id":89,"doc_module":4,"doc_module_name":25,"category_name":90,"show_sort_weight":91,"slug":92},5,"Comic",60,"comic",{"id":94,"doc_module":4,"doc_module_name":25,"category_name":95,"show_sort_weight":96,"slug":97},6,"Technology",50,"technology",{"id":99,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":100,"slug":101},7,40,"healthcare",{"id":103,"doc_module":4,"doc_module_name":25,"category_name":104,"show_sort_weight":105,"slug":106},8,"Research & Report",30,"research-report",{"id":108,"doc_module":4,"doc_module_name":25,"category_name":109,"show_sort_weight":110,"slug":111},9,"Religion & Spirituality",20,"religion-spirituality",{"id":110,"doc_module":4,"doc_module_name":25,"category_name":113,"show_sort_weight":110,"slug":114},"World Cup","world-cup",{"id":116,"doc_module":4,"doc_module_name":25,"category_name":117,"show_sort_weight":116,"slug":118},10,"Lifestyle","lifestyle",{"id":120,"doc_module":4,"doc_module_name":25,"category_name":121,"show_sort_weight":89,"slug":122},19,"General","general",{"code":4,"msg":74,"data":124},{"doc_id":71,"user_id":125,"nickname":42,"user_avatar":126,"doc_module":4,"category_id":99,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":127,"file_id":128,"file_url":129,"file_type":130,"file_size":131,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":108,"language":132,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":133,"faqs":134,"seo_title":135,"seo_description":12,"update_tm":136,"read_time":137},8796095461564,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Cancer Gene [Therapy](Therapy www.nature.com/cgt)[ www.nature.com/cgt](Therapy www.nature.com/cgt)  \nREVIEW ARTICLE OPEN   \nTargeting KRASG12D mutation in non-small cell lung cancer: molecular mechanisms and therapeutic potential  \nYining Tang 1, Xi Pu1, Xiao Yuan1, Zhonghao Pang2, Feng Li 2 ✉ and Xu Wang 1 ✉  \n© The Author(s) 2024  \n|  |  |  |\n| --- | --- | --- |\n|  | Lung malignant tumors are a type of cancer with high incidence and mortality rates worldwide. Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung malignant tumors, and most patients are diagnosed at advanced stages, leading to poor prognosis. Over the past decades, various oncogenic driver alterations associated with lung cancer have been identified, each of which can potentially serve as a therapeutic target. Rat sarcoma (RAS) genes are the most commonly mutated oncogenes in human cancers, with Kirsten rat sarcoma (KRAS) being the most common subtype. The role of KRAS oncogene in NSCLC is still not fully understood, and its impact on prognosis remains controversial. Despite the significant advancements in targeted therapy and immune checkpoint inhibitors (ICI) that have transformed the treatment landscape of advanced NSCLC in recent years, targeting KRAS (both directly and indirectly) remains challenging and is still under intensive research. In recent years, significant progress has been made in the development of targeted drugs targeting the NSCLC KRASG12C mutant subtype. However, research progress on target drugs for the more common KRASG12D subtype has been slow, and currently, no specific drugs have been approved for clinical use, and many questions remain to be answered, such as the mechanisms of resistance in this subtype of NSCLC, how to better utilize combination strategies with multiple treatment modalities, and whether KRASG12D inhibitors offer substantial efficacy |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n| in the treatment of advanced NSCLC patients. |  |  |\n|  | Cancer Gene Therapy (2024) 31:961–969; [https://doi.org/10.1038/s41417-024-00778-4](https://doi.org/10.1038/s41417-024-00778-4) |  |\n|  |  |  |\n\nINTRODUCTION  \nLung cancer is the most common and deadly cancer worldwide [1] . Non-small cell lung cancer (NSCLC) accounts for ~80% of all lung cancers, with lung adenocarcinoma (LUAD) being the most common histological subtype, often accompanied by oncogenicdriver mutations [2] . With the development of molecular targeted therapy, some LUAD patients can benefit from specific drugs targeting multiple gene loci, such as EGFR, ALK, ROS1, etc. The RAS proteins (H-RAS, K-RAS, and N-RAS) are GTPases that regulate various cellular activities, including proliferation, survival, growth, migration, differentiation, and cytoskeletal dynamics, through signal transduction pathways. When mutated, RAS proteins remain activated, leading to excessive activation of downstream signaling pathways and ultimately triggering tumor formation. Among them, KRAS gene mutations are found in ~30% of lung adenocarcinomas (LUAD) . Unlike lung cancers with mutated EGFRand ALK expressions, KRAS has long been considered a challenging therapeutic target, even regarded as “undruggable”. It is generally believed that the difficulty in developing direct KRAS inhibitors is due in part to the pico-molar affinity of GTP and GDP for KRAS (which have much higher cellular concentrations) and to the lack of suitable deep pockets for conformational regulation [3] . Therefore, the development of targeted drugs for KRAS has been difficult for many years. This dilemma was broken in 2013 when American chemical biologist Kevan Shokat discovered that when KRASG12C protein is in the inactive GDP-bound state, the switch II  \ndomain (SIIP) of its mutated cysteine residue exhibits a pocket structure that can covalently bind to small molecule drugs [4] . These targeted drugs are now collectively known as KRASG12","cbCaiorHtAsSfckn","https://ap.wps.com/l/cbCaiorHtAsSfckn","pdf",812047,"English","# Introduction\n## KRAS mutations and NSCLC molecular context\n## KRASG12C inhibitors and rationale for KRASG12D targeting\n# Characteristics of KRAS mutations in NSCLC\n## Molecular background of KRAS conformational cycling","[{\"question\":\"What molecular properties of KRAS are relevant to drug development?\",\"answer\":\"KRAS cycles between active GTP-bound and inactive GDP-bound conformations, and mutated KRAS remains activated, driving downstream signaling that supports tumor formation. The review also notes that developing direct KRAS inhibitors was historically difficult, in part due to nucleotide binding characteristics and lack of suitable regulatory pockets.\"}]","Targeting KRASG12D mutation in non-small cell lung cancer - molecular mechanisms and therapeutic potential - review article | PDF",1790031945,23]