[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-327818-105":59,"doc-detail-327818-en":130},{"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":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","targeting-ng2-relieves-the-resistance-of-braf-mutant-thyroid-cancer-cells-to-braf-inhibitors","Targeting NG2 relieves the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitors","","BRAFV600E drives thyroid cancer biology but BRAF-targeted small-molecule therapy is frequently limited by acquired resistance. This study identifies nerve/glial antigen 2 (NG2, CSPG4) as up-regulated in thyroid cancers and increasing with progression in a BRAFV600E-driven mouse model. NG2 knockout does not alter tumor growth yet markedly improves sensitivity to the BRAF inhibitor PLX4720. Mechanistically, NG2 loss suppresses PLX4720-induced ERK feedback activation of multiple RTKs, and combined kinase inhibition with Sorafenib or Lenvatinib plus PLX4720 offers an effective therapeutic strategy.",{"@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":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/targeting-ng2-relieves-the-resistance-of-braf-mutant-thyroid-cancer-cells-to-braf-inhibitors/327818/",{"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-ng2-relieves-the-resistance-of-braf-mutant-thyroid-cancer-cells-to-braf-inhibitors/327818.png","ImageObject",300,407,{"name":92,"@type":93},"Ivy","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-27","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role does BRAFV600E play in thyroid cancer therapy resistance?","Question",{"text":112,"@type":113},"BRAFV600E is the most prevalent genetic alteration in thyroid cancer, and although BRAF inhibitors can initially work, acquired resistance commonly limits clinical efficacy.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does NG2 affect the response of BRAF-mutant thyroid cancer cells to BRAF inhibitors?",{"text":117,"@type":113},"NG2 knockout significantly improves sensitivity to the BRAF inhibitor PLX4720, without markedly affecting tumor growth.",{"name":119,"@type":110,"acceptedAnswer":120},"What mechanism links NG2 to resistance caused by BRAF inhibitor–mediated feedback activation?",{"text":121,"@type":113},"Blocking ERK-dependent feedback by a BRAF inhibitor can activate receptor tyrosine kinase (RTK) signaling, and NG2 knockout attenuates this PLX4720-driven feedback activation of several RTKs.","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},327818,1790413211,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},549758252649,"https://ap-avatar.wpscdn.com/avatar/8000253669c5317157?_k=1778319167496531819","Cellular and Molecular Life Sciences (2024) 81:238  \n[https://doi.org/10.1007/s00018-024-05280-6](https://doi.org/10.1007/s00018-024-05280-6) Cellular and Molecular Life Sciences  \nORIGINAL ARTICLE  \nTargeting NG2 relieves the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitors  \nFang Sui1,2 · Guanjie Wang1 · Juan Liu1 · Mengmeng Yuan1 · Pu Chen1 · Yao Yao1 · Shaoqiang Zhang2 · Meiju Ji3 · Peng Hou1,4  \nReceived: 7 December 2023 / Revised: 4 May 2024 / Accepted: 13 May 2024 © The Author(s) 2024  \nAbstract  \nBRAFV600E represents a constitutively active onco-kinase and stands as the most prevalent genetic alteration in thyroid cancer. However, the clinical efficacy of small-molecule inhibitors targeting BRAFV600E is often limited by acquired resistance. Here, we find that nerve/glial antigen 2 (NG2), also known as chondroitin sulfate proteoglycan 4 (CSPG4), is up-regulated in thyroid cancers, and its expression is increased with tumor progression in a BRAFV600E-driven thyroid cancer mouse model. Functional studies show that NG2 knockout almost does not affect tumor growth, but significantly improves the response of BRAF-mutant thyroid cancer cells to BRAF inhibitor PLX4720 . Mechanistically, the blockade of ERK-dependent feedback by BRAF inhibitor can activate receptor tyrosine kinase (RTK) signaling, causing the resistance to this inhibitor. NG2 knockout attenuates the PLX4720-mediated feedback activation of several RTKs, improving the sensitivity of BRAF-mutant thyroid cancer cells to this inhibitor. Based on this finding, we propose and demonstrate an alternative strategy for targeting NG2 to effectively treat BRAF-mutant thyroid cancers by combining multiple kinase inhibitor (MKI) Sorafenib or Lenvatinib with PLX4720 . Thus, this study uncovers a new mechanism in which NG2 contributes to the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitor, and provides a promising therapeutic option for BRAF-mutant thyroid cancers.  \nKeywords BRAF mutations · NG2 · Thyroid cancer · Receptor tyrosine kinase (RTK) · Feedback activation  \nFang Sui and Guanjie Wang contributed equally to this work.  \n􀀍 Meiju Ji[mjji0409@163.com](mjji0409@163.com)  \n􀀍 Peng Hou[phou@xjtu.edu.cn](phou@xjtu.edu.cn)  \n1 Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province 710061, P.R. China  \n2 Department of Otorhinolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province 710061, P.R. China  \n3 Center for Translational Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province 710061, P.R. China  \n4 Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, P.R. China  \nIntroduction  \nBRAFV600E mutation is the most common genetic event in thyroid cancers [1–3]. Thyroid cancers harboring this mutation have been reported to exhibit more aggressive tumor behaviors, including extrathyroidal extension, lymph node metastases, loss of iodine avidity, and higher risks of recurrence and disease-related death [4–6]. Thus, the use of small molecular inhibitors targeting mutant BRAF and its downstream effector MEK has become a major therapeutic strategy for BRAF-mutant thyroid cancers [4–6] .  \nThe initial approved selective inhibitor targeting mutant BRAF is vemurafenib (PLX4032), showcasing promising early therapeutic benefits [7] . Despite the improved survival observed in patients with BRAF-mutant metastatic melanomas by the use of BRAF inhibitors [7], their efficacy is limited in individuals with thyroid cancer [8, 9] . This limitation can be attributed to the rebound effect in extracellular signal-regulated kinase (ERK) activity, which is mediated by heightened HER2/HER3 signaling [9] . Lapatinib as a small  \n1 3  \nmolecule dual tyrosine kinase inhibitor of EGFR and HER-2 has been demonstrated the ability to p","cbCaioOubrr2z5yk","https://ap.wps.com/l/cbCaioOubrr2z5yk","pdf",5748579,15,"English","# Introduction\n## BRAFV600E in thyroid cancer and limits of BRAF inhibitors\n## NG2 and RTK signaling as resistance candidates\n# Results\n## NG2 expression correlates with thyroid cancer progression","[{\"question\":\"What role does BRAFV600E play in thyroid cancer therapy resistance?\",\"answer\":\"BRAFV600E is the most prevalent genetic alteration in thyroid cancer, and although BRAF inhibitors can initially work, acquired resistance commonly limits clinical efficacy.\"},{\"question\":\"How does NG2 affect the response of BRAF-mutant thyroid cancer cells to BRAF inhibitors?\",\"answer\":\"NG2 knockout significantly improves sensitivity to the BRAF inhibitor PLX4720, without markedly affecting tumor growth.\"},{\"question\":\"What mechanism links NG2 to resistance caused by BRAF inhibitor–mediated feedback activation?\",\"answer\":\"Blocking ERK-dependent feedback by a BRAF inhibitor can activate receptor tyrosine kinase (RTK) signaling, and NG2 knockout attenuates this PLX4720-driven feedback activation of several RTKs.\"}]","Targeting NG2 relieves the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitors | PDF",1789978126,38]