[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-365969-105":59,"doc-detail-365969-en":131},{"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":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","the-complex-journey-of-targeting-ras-in-oncology-review","The complex journey of targeting RAS in oncology - Review","","Given the prevalence of RAS mutations across cancers, personalized treatment strategies guided by molecular markers are crucial. Farnesyltransferase inhibitors are being explored but face toxicity and limited effectiveness. Emerging approaches include direct inhibitors with pathway modulators, RNA interference, and gene-editing. Targeting RAS remains difficult due to structural features such as the G domain and variability in patient responses. Advances including sotorasib and adagrasib for KRAS G12C are offset by adaptive resistance and the need for isoform selectivity.",{"@graph":69,"@context":123},[70,84,106],{"@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/the-complex-journey-of-targeting-ras-in-oncology-review/365969/",{"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/the-complex-journey-of-targeting-ras-in-oncology-review/365969.png","ImageObject",300,407,{"name":92,"@type":93},"Melati","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-01","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"Why is targeting RAS considered essential in oncology?","Question",{"text":113,"@type":114},"RAS mutations occur across many cancer types and promote constitutive activation of downstream signaling, driving tumorigenesis such as uncontrolled proliferation and altered microenvironmental cues.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What obstacles limit the development and effectiveness of RAS inhibitors?",{"text":118,"@type":114},"Key barriers include limited drug-binding pocket availability, very high nucleotide affinity, toxicity concerns, and adaptive resistance that reduces sustained clinical efficacy.",{"name":120,"@type":111,"acceptedAnswer":121},"What new therapeutic strategies beyond farnesyltransferase inhibitors are under investigation?",{"text":122,"@type":114},"The document highlights approaches such as direct inhibitors combined with pathway modulators, RNA interference, and gene-editing technologies to modulate RAS-related signaling.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},365969,1790217908,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},962085570644,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","Wasiak etal. BMC Cancer (2025) 25:1053 [https://doi.org/10.1186/s12885-025-14033-y](https://doi.org/10.1186/s12885-025-14033-y)  \nBMC Cancer  \n REVIEW Open Access  \nThe complex journey of targeting RASin oncology  \nKatarzyna Wasiak1,2*, Damian Ciunowicz1,4, Amelia Kierasińska‑Kałka 1,2, Marta Węgierska1,2, Marcin Pacholczyk 1,3, Piotr Rieske1,2 and Ewelina Stoczyńska‑Fidelus1,4  \nAbstract  \nGiven the prevalence of RAS mutations in various cancers, personalized therapeutic approaches, guided by molecular markers, are essential. Farnesyltransferase inhibitors (FTIs) have emerged as potential therapeutic options; however, they also face obstacles such as toxicity and limited efficacy. Alternative strategies, such as direct inhibitors combined with pathway modulators, RNA interference, and gene‑editing technologies, are under clinical investigation. The targeting of RAS, complicated by its structural nuances, particularly in the G domain, has advanced with the identifica‑ tion of druggable pockets such as the SW‑II pocket. This breakthrough has led to the development of targeted thera‑ peutics, such as sotorasib and adagrasib, for KRAS G12C‑mutated non‑small cell lung cancer (NSCLC) . However, these advancements face challenges, including adaptive resistance and the necessity for isoform selectivity. New inhibi‑ tors, such as LY3537982 or GDC‑6036, are promising, but achieving effective and selective RAS inhibition remains a significant challenge. Additionally, clinical trials have highlighted variability in patient responses, attributing limited treatment efficacy to resistance mechanisms, including on‑target mutations and off‑target pathway activations.  \nFinally, the RAS oncogene, traditionally viewed as predominantly pro‑cancerous, plays a complex role in oncogen‑ esis, with recent evidence suggesting context‑dependent effects, such as inducing senescence in certain cells. This shift in understanding underscores the therapeutic potential of manipulating the interplay between RAS andTP53 mutations in cancer. In conclusion, the complexity of effectively targeting the RAS‑RAF‑ERK pathway is exacerbated by the diverse resistance mechanisms. Challenges such as off‑target effects and delivery issues remain significant bar‑ riers in the introduction of effective therapies based on RAS inhibitors. This overview highlights the evolving nature of targeting RAS in cancer therapy.  \nKeywords RAS proteins, KRAS, HRAS, NRAS, Oncogene, Cancer, Therapy, Protein structure, Drug discovery, Senescence  \n*Correspondence:  \nKatarzyna Wasiak [katarzyna.wasiak@umed.lodz.pl](katarzyna.wasiak@umed.lodz.pl)  \n1 Department of Research and Development, Personather Ltd., Inwestycyjna 7, Konstantynow Lodzki 95 ‑ 050, Poland  \n2 Department of Tumor Biology, Chair of Medical Biology, Medical University of Lodz, Zeligowskiego 7/9 St., Lodz 90 ‑ 752, Poland  \n3 Department of Systems Biology and Engineering, Silesian University of Technology, Akademicka 16, Gliwice 44 ‑ 100, Poland  \n4 Department of Molecular Biology, Chair of Medical Biology, Medical University of Lodz, Zeligowskiego 7/9 St., Lodz 90 ‑ 752, Poland  \nIntroduction  \nThe RAS family of small GTPases has long been the subject of intense research in oncology due to its central role in the development and progression of various cancer types. Oncogenic mutations of RAS, particularly KRAS, are found in a significant proportion of human cancers, including gastrointestinal (\u003C 50%), pancreatic (13.37%), and lung (12.75%) cancers (Fig. 1) [1]. Across all databases, KRAS was the predominant variant affecting patients, accounting for 63–82% of the cohort. Conversely, HRAS constituted the smallest proportion,  \n© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, prov","cbCaiiPfUpFJUPPM","https://ap.wps.com/l/cbCaiiPfUpFJUPPM","pdf",4102268,29,"English","# Introduction\n## RAS mutations and oncogenic activation\n## Challenges for small-molecule inhibitor development\n# Abstract","[{\"question\":\"Why is targeting RAS considered essential in oncology?\",\"answer\":\"RAS mutations occur across many cancer types and promote constitutive activation of downstream signaling, driving tumorigenesis such as uncontrolled proliferation and altered microenvironmental cues.\"},{\"question\":\"What obstacles limit the development and effectiveness of RAS inhibitors?\",\"answer\":\"Key barriers include limited drug-binding pocket availability, very high nucleotide affinity, toxicity concerns, and adaptive resistance that reduces sustained clinical efficacy.\"},{\"question\":\"What new therapeutic strategies beyond farnesyltransferase inhibitors are under investigation?\",\"answer\":\"The document highlights approaches such as direct inhibitors combined with pathway modulators, RNA interference, and gene-editing technologies to modulate RAS-related signaling.\"}]","The complex journey of targeting RAS in oncology - Review | PDF",1790163233,73]