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Emerging directions include non-covalent KRAS G12D inhibitors, probody bispecific antibodies, drug–peptide conjugates for neoantigen presentation, and adoptive cell therapy successes in breast and pancreatic cancers.",{"@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/targeting-the-undruggable-driver-protein-kras-in-epithelial-cancers-current-perspective/406686/",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-the-undruggable-driver-protein-kras-in-epithelial-cancers-current-perspective/406686.png","ImageObject",300,407,{"name":42,"@type":43},"CatatanPagi","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-03","2026-09-28",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",9,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"Why does targeting KRAS in epithelial cancers remain challenging?","Question",{"text":63,"@type":64},"KRAS is an intracellular driver, and while small molecules can penetrate cells, they often cause off-target effects and resistance. Biologics may be more specific but face cellular entry limitations.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What therapeutic problem does KRAS mutation create for EGFR-based treatment?",{"text":68,"@type":64},"KRAS is downstream of EGFR, so activating mutations in KRAS can make anti-EGFR therapy ineffective. Patients may still develop resistance over time through KRAS evolution.",{"name":70,"@type":61,"acceptedAnswer":71},"What recent breakthroughs does the review highlight for KRAS-directed therapies?",{"text":72,"@type":64},"It highlights non-covalent KRAS G12D-specific inhibitors, probody bispecific antibodies, drug–peptide conjugates for MHC-restricted neoantigen presentation, and advances in adoptive cell therapy in breast and pancreatic cancers.","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},406686,1791302984,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,119,122,126],{"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":111,"doc_module":4,"doc_module_name":25,"category_name":112,"show_sort_weight":113,"slug":114},8,"Research & Report",30,"research-report",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},"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":108,"preview_page_count":4},962090894170,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","cells  \nReview  \nTargeting the `Undruggable' Driver Protein, KRAS, in Epithelial Cancers: Current Perspective  \nKuen Kuen Lam 1, Siew Heng Wong 2 and Peh Yean Cheah 1,3,4, *  \nCitation: Lam, K.K.; Wong, S.H.; Cheah, P.Y. Targeting the `Undruggable' Driver Protein, KRAS, in Epithelial Cancers: Current Perspective. Cells 2023, 12, 631 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cells12040631  \nAcademic Editors: Amancio Carnero, Sandra Muñoz-Galv¡n and Jos²  \nM. Garc½a-Heredia  \nReceived: 29 November 2022  \nRevised: 30 January 2023  \nAccepted: 10 February 2023  \nPublished: 15 February 2023  \nCopyright: © 2023 by the authors. 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 Colorectal Surgery, Singapore General Hospital, Singapore 169856, Singapore  \n2 J W BioSciences, Singapore 680226, Singapore  \n3 Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117549, Singapore  \n4 Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore  \n* Correspondence: [cheah.peh.yean@sgh.com.sg](cheah.peh.yean@sgh.com.sg)  \nAbstract: This review summarizes recent development in synthetic drugs and biologics targeting intracellular driver genes in epithelial cancers, focusing on KRAS, and provides a current perspective and potential leads for the field. Compared to biologics, small molecule inhibitors (SMIs) readily penetrate cells, thus being able to target intracellular proteins. However, SMIs frequently suffer from pleiotropic effects, off-target cytotoxicity and invariably elicit resistance. In contrast, biologics are much larger molecules limited by cellular entry, but if this is surmounted, they may have more specific effects and less therapy-induced resistance. Exciting breakthroughs in the past two years include engineering of non-covalent KRAS G12D-specific inhibitor, probody bispecific antibodies, drug–peptide conjugate as MHC-restricted neoantigen to prompt immune response by T-cells, and success in the adoptive cell therapy front in both breast and pancreatic cancers.  \nKeywords: KRAS; colorectal carcinomas; internal cancer drivers; small molecule inhibitor; macromolecular drug; adoptive cell therapy; bispecific antibody; antibody–drug conjugate; cytosolic antibodies  \n1. Introduction  \nMost (74%) of the genes strongly implicated in cancer by COSMIC encoded intracellular proteins which primarily localized to the cytosol or nucleoplasm. The U.S. Food and Drug Administration has approved drugs targeting human proteins from 618 genes, in which 535 proteins are targeted by synthetic small molecule inhibitors (SMIs) and only 108 are targeted by biologics. Most of these targets are predicted to be membrane proteins (59%), and 16% are secreted [1] . Thus, a substantial number of intracellular targets remain untargeted, which opens potential therapeutic opportunities.  \nCancer is a major debilitating disease ([https://seer.cancer.gov/statfacts/html/colorect](https://seer.cancer.gov/statfacts/html/colorect). html) [2] . Colorectal cancer (CRC) is the third most frequent cancer and a leading cause of cancer mortality worldwide, attributable mainly to metastasis to distal organs such as liver and lung. Current chemotherapeutic drugs for advanced CRC have a dismayed success rate of less than 30%[3–5] . Despite better median survival in responders in the past two decades, respond rate to chemotherapy remained stagnant [6] . Patients who are not responsive to first-line chemotherapeutic drugs and whose KRAS status is wildtype are sometimes offered anti-epidermal growth factor receptor (anti-EGFR) therapy such as Cetuximaband Panitumumab. KRAS is downstream of EGFR, and henc","cbCaid4SUnOozaP5","https://ap.wps.com/l/cbCaid4SUnOozaP5","pdf",931664,16,"English","# Abstract\n# Introduction\n## Intracellular cancer driver targetability\n## KRAS biology and therapeutic relevance in colorectal cancer","[{\"question\":\"Why does targeting KRAS in epithelial cancers remain challenging?\",\"answer\":\"KRAS is an intracellular driver, and while small molecules can penetrate cells, they often cause off-target effects and resistance. Biologics may be more specific but face cellular entry limitations.\"},{\"question\":\"What therapeutic problem does KRAS mutation create for EGFR-based treatment?\",\"answer\":\"KRAS is downstream of EGFR, so activating mutations in KRAS can make anti-EGFR therapy ineffective. Patients may still develop resistance over time through KRAS evolution.\"},{\"question\":\"What recent breakthroughs does the review highlight for KRAS-directed therapies?\",\"answer\":\"It highlights non-covalent KRAS G12D-specific inhibitors, probody bispecific antibodies, drug–peptide conjugates for MHC-restricted neoantigen presentation, and advances in adoptive cell therapy in breast and pancreatic cancers.\"}]","Targeting the 'Undruggable' Driver Protein, KRAS, in Epithelial Cancers: Current Perspective | PDF",1790567271]