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MAPK activation is mainly driven by genomic alterations in RAS and BRAF, where BRAF functions downstream of RAS to transmit oncogenic signaling through MEK and ERK. Across cancers, BRAF alterations include gain-of-function mutations, copy-number changes, and structural rearrangements. The article reviews forms of BRAF alterations and strategies for inhibiting them in patients with cancers of different origins.",{"@graph":69,"@context":122},[70,84,105],{"@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/targeting-the-multifaceted-braf-in-cancer-new-directions/332242/",{"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/targeting-the-multifaceted-braf-in-cancer-new-directions/332242.png","ImageObject",300,407,{"name":92,"@type":93},"Noah","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-23","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the role of BRAF in the MAPK signaling pathway and cancer?","Question",{"text":112,"@type":113},"BRAF is a downstream effector of MAPK signaling that propagates oncogenic activity through MEK and ERK. In cancer, BRAF is frequently altered and can support pro-growth and pro-survival signaling.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How are BRAF alterations classified in this article?",{"text":117,"@type":113},"The article describes three classes of activating BRAF alterations based on RAS dependency, dimerization status, and kinase activity: Class I (p.V600), Class II (non-p.V600, homodimers, RAS-independent), and Class III (non-p.V600, heterodimerization, RAS-dependent).",{"name":119,"@type":110,"acceptedAnswer":120},"Which BRAF-targeted therapies are most relevant to Class I BRAF alterations?",{"text":121,"@type":113},"For tumors with Class I alterations (p.V600 hotspot mutations), BRAF-targeting precision therapeutics are described as effective, including BRAF inhibitors and combinations of BRAF/MEK inhibitors.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},332242,1790194560,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":34,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":34,"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":143,"read_time":144,"preview_page_count":4},8796095462418,"https://ap-avatar.wpscdn.com/avatar/80000253c1241d02b47?x-image-process=image/resize,m_fixed,w_180,h_180&k=1778826106357471780","[www.oncotarget.com](www.oncotarget.com) Oncotarget, 2024, Vol. 15, pp: 486-492  \nResearch Perspective  \nTargeting the multifaceted BRAF in cancer: New directions  \nEamon Toye 1,2,3, Alexander Chehrazi-Raffle4, Justin Hwang 1,2 and Emmanuel S . Antonarakis 1,2  \n1 Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA 2 Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA 3 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19146, USA 4City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA  \nCorrespondence to: Emmanuel S. Antonarakis, [email](email: anton401@umn.edu)[: anton401@umn.edu](email: anton401@umn.edu)  \nJustin Hwang, email: [jhwang@umn.edu](jhwang@umn.edu)  \nKeywords: BRAF; MAPK; pan-cancer; precision oncology; genomics  \nReceived: July 01, 2024 Accepted: July 07, 2024 Published: July 16, 2024  \nCopyright: © 2024 Toye et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.  \nABSTRACT  \nActivating mutations in the mitogen-activated protein kinase (MAPK) pathway represent driver alterations governing tumorigenesis, metastasis, and therapy resistance. MAPK activation predominantly occurs through genomic alterations in RASand BRAF. BRAF is an effector kinase that functions downstream of RAS and propagates this oncogenic activity through MEK and ERK. Across cancers, BRAF alterations include gain-of-function mutations, copy-number alterations, and structural rearrangements. In cancer patients, BRAF-targeting precision therapeutics are effective against Class I BRAF alterations (p.V600 hotspot mutations) in tumors such as melanomas, thyroid cancers, and colorectal cancers. However, numerous non-Class I BRAF inhibitors are also in development and have been explored in some cancers. Here we discuss the diverse forms of BRAF alterations found in human cancers and the strategies to inhibit them in patients harboring cancers of distinct origins.  \nINTRODUCTION  \nBRAF is an effector of MAPK signaling  \nThe mitogen-activated protein kinase (MAPK) pathway is a vital cell signaling pathway [1] . The MAPK pathway regulates cellular functions ranging from cell growth and proliferation to tissue repair and wound healing [2–4] . Functional members of this pathway are the cytoplasmic serine/threonine kinases RAS, RAF, MEK, and ERK. Canonical activation of receptor tyrosine kinases leads to RAS-GDP phosphorylation, creating activated RASGTP. This in turn phosphorylates RAF, which dimerizesand then phosphorylates MEK1/2 . Phosphorylated MEK1/2 then activates ERK1/2, which regulates cellular growth, proliferation, and cell death [5–7] . There are three distinct isoforms of the RAF proteins encoded by theARAF, BRAF, and RAF1 (also known as CRAF) genes [8] . Each of these isoforms contains the same conserved regions (CR): the RAS-binding domain (CR1), regulatory domain (CR2),  \nand functional kinase domain (CR3) [9] . Although all RAF kinases promote MAPK signaling, BRAF is the most consistently altered RAF family gene across human cancers.  \nBRAF in cancer  \nDue to these pro-growth and pro-survival functions, cancer cells can develop “oncogenic addiction” towards BRAF’s signaling activity [10, 11]. Initially characterized in melanomas, various groups including ours have identified activating BRAF alterations across multiple cancers [12–19] . Based on the American Association for Cancer Research’s (AACR) Genomics Evidence Neoplasia Information Exchange (GENIE, version 15.1) dataset, BRAF alterations are observed in several human malignancies, including 44% of thyroid cancers, 35% of melanomas, and 12% of colorectal cancers; with multiple other major cancer types exhibiting lower frequencies of BRAF alterations (Figure 1A) . Consistent with these geno","cbCaijUn2czwKQ8C","https://ap.wps.com/l/cbCaijUn2czwKQ8C","pdf",1275051,"English","# Targeting the multifaceted BRAF in cancer: New directions\n## Research Perspective\n## Introduction\n### BRAF is an effector of MAPK signaling\n### BRAF in cancer\n### Classes of BRAF alterations in cancer\n## Figure 1: BRAF alteration frequencies and classifications","[{\"question\":\"What is the role of BRAF in the MAPK signaling pathway and cancer?\",\"answer\":\"BRAF is a downstream effector of MAPK signaling that propagates oncogenic activity through MEK and ERK. In cancer, BRAF is frequently altered and can support pro-growth and pro-survival signaling.\"},{\"question\":\"How are BRAF alterations classified in this article?\",\"answer\":\"The article describes three classes of activating BRAF alterations based on RAS dependency, dimerization status, and kinase activity: Class I (p.V600), Class II (non-p.V600, homodimers, RAS-independent), and Class III (non-p.V600, heterodimerization, RAS-dependent).\"},{\"question\":\"Which BRAF-targeted therapies are most relevant to Class I BRAF alterations?\",\"answer\":\"For tumors with Class I alterations (p.V600 hotspot mutations), BRAF-targeting precision therapeutics are described as effective, including BRAF inhibitors and combinations of BRAF/MEK inhibitors.\"}]","Targeting the multifaceted BRAF in cancer - New directions | PDF",1789997498,18]