[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-380711-105":59,"doc-detail-380711-en":129},{"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":122,"head_meta":124,"extra_data":126,"updated_unix":128},105,"en","nucleic-acid-based-approaches-to-tackle-kras-mutant-cancers","Nucleic Acid-Based Approaches to Tackle KRAS Mutant Cancers","","Activating mutations in KRAS drive persistent efforts to develop drugs that can effectively inhibit KRAS activity. This review explains how recent advances in RNA and nucleic acid chemistry and delivery formulations changed the strategy from the historical “undruggable” KRAS concept. It surveys progress in targeting KRAS mutant tumors and details nucleic acid-based therapeutic mechanisms, key challenges, and the current landscape of clinical trials.",{"@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/nucleic-acid-based-approaches-to-tackle-kras-mutant-cancers/380711/",{"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/nucleic-acid-based-approaches-to-tackle-kras-mutant-cancers/380711.png","ImageObject",300,407,{"name":92,"@type":93},"Well Done","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-24",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},"Why were KRAS mutations historically difficult to target with drugs?","Question",{"text":111,"@type":112},"Direct inhibition was challenging because KRAS binds guanine nucleotides with very high (picomolar) affinity, GDP/GTP are abundant in cells, and the protein surface lacks favorable small-molecule binding sites.","Answer",{"name":114,"@type":109,"acceptedAnswer":115},"What changed the approach to KRAS inhibition in recent years?",{"text":116,"@type":112},"Advances in understanding RNA/nucleic-acid chemistry and improved delivery formulations shifted the paradigm toward nucleic acid-based therapeutics for KRAS mutant cancers.",{"name":118,"@type":109,"acceptedAnswer":119},"Which KRAS mutations have recent direct inhibitors focused on, and what remains unresolved?",{"text":120,"@type":112},"Breakthroughs have targeted mutant KRAS G12C and G12D, but other KRAS mutants beyond these still remain elusive for drug development.","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},380711,1790241406,{"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":36},5909892210082,"https://ap-avatar.wpscdn.com/avatar/56001069da27c9f41e8?x-image-process=image/resize,m_fixed,w_180,h_180&k=1789614185077863061","Review  \nNucleic Acid-Based Approaches to Tackle KRAS Mutant Cancers  \nJimi Kim 1,2  \nCitation: Kim, J. Nucleic Acid-Based Approaches to Tackle KRAS Mutant Cancers. Int. J. Mol. Sci. 2023, 24, 16933. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms242316933  \nAcademic Editor: Silvia Catuogno  \nReceived: 1 November 2023  \nRevised: 24 November 2023  \nAccepted: 27 November 2023  \nPublished: 29 November 2023  \nCopyright: © 2023 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Department of Life Sciences, Gachon University, Seongnam 13120, Republic of Korea; [zimic@gachon.ac.kr](zimic@gachon.ac.kr)  \n2 Department of Health Science and Technology, GAIHST, Lee Gil Ya Cancer and Diabetes Institute, Incheon 21999, Republic of Korea  \nAbstract: Activating mutations in KRAS are highly relevant to various cancers, driving persistent efforts toward the development of drugs that can effectively inhibit KRAS activity. Previously, KRAS was considered `undruggable'; however, the recent advances in our understanding of RNA and nucleic acid chemistry and delivery formulations have sparked a paradigm shift in the approach to KRAS inhibition. We are currently witnessing a large wave of next-generation drugs for KRAS mutant cancers—nucleic acid-based therapeutics. In this review, we discuss the current progress in targeting KRAS mutant tumors and outline significant developments in nucleic acid-based strategies. We delve into their mechanisms of action, address existing challenges, and offer insights into the current clinical trial status of these approaches. We aim to provide a thorough understanding of the potential of nucleic acid-based strategies in the field of KRAS mutant cancer therapeutics.  \nKeywords: oncogenic KRAS; cancer therapy; RNA therapeutics; RNAi; CRISPR-Cas; mRNA vaccine  \n1. Introduction to Oncogenic KRAS  \nKRAS, a relevant proto-oncogene, was initially discovered in the early 1980s as a transforming human DNA fragment that is homologous to Kirsten sarcoma viruses (Kirsten ras or v-Kras) . It is frequently mutated, with these mutations commonly implicated in the pathogenesis of pancreatic cancers, colorectal cancers (CRC), and lung adenocarcinoma [1] .  \nKRAS is a 21 kDa small guanine triphosphatase (GTPase) that plays a pivotal role in cellular pathways governing cell survival, proliferation, and differentiation. It oscillates between the guanine diphosphate (GDP)-bound `OFF' state and the guanine triphosphate (GTP)-bound `ON' state. In its `ON' state, KRAS exhibits enhanced affinity for multiple effectors including Raf, phosphatidylinositol 3-kinase (PI3K), and Ral guanine nucleotide dissociation stimulator (RalGDS), thus activating downstream signaling [2–5] .  \nThe biological function of KRAS is carried by the G domain, which is comprised of residues 1–166 . The G domain harbors a phosphate-binding loop (p loop), and two switch regions (Switch I and II) that interact with the nucleotide. The release of the 􀀍-phosphate through hydrolysis induces a conformation change in the two switch regions, resulting in a GDP-specific form. In addition to the G domain, KRAS has a flexible C-terminal domain, known as the hypervariable region (HVR), which is critical for its membrane localization (Figure 1a,b) [6,7] .  \nOncogenic mutations in KRAS primarily occur at residues G12, G13, and Q61 . These mutations impair the hydrolysis of the 􀀍-phosphate of GTP to GDP, causing KRAS to remain persistently `ON', thereby constitutively activating downstream signaling and driving cellular transformation (Figure 1c,d) [8,9] .  \nBased on the comprehensive understanding of the molecular requirements for KRAS activity, various attemp","cbCait2FVvmXXfg3","https://ap.wps.com/l/cbCait2FVvmXXfg3","pdf",1651822,16,"English","# Abstract\n# Introduction to Oncogenic KRAS\n## KRAS biology and activation cycle\n## Oncogenic KRAS mutations and drug-development challenges\n## Rationale for nucleic acid-based strategies\n# Review scope and therapeutic directions","[{\"question\":\"Why were KRAS mutations historically difficult to target with drugs?\",\"answer\":\"Direct inhibition was challenging because KRAS binds guanine nucleotides with very high (picomolar) affinity, GDP/GTP are abundant in cells, and the protein surface lacks favorable small-molecule binding sites.\"},{\"question\":\"What changed the approach to KRAS inhibition in recent years?\",\"answer\":\"Advances in understanding RNA/nucleic-acid chemistry and improved delivery formulations shifted the paradigm toward nucleic acid-based therapeutics for KRAS mutant cancers.\"},{\"question\":\"Which KRAS mutations have recent direct inhibitors focused on, and what remains unresolved?\",\"answer\":\"Breakthroughs have targeted mutant KRAS G12C and G12D, but other KRAS mutants beyond these still remain elusive for drug development.\"}]","Nucleic Acid-Based Approaches to Tackle KRAS Mutant Cancers | PDF"]