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Targeted RAF and MEK inhibitors show activity in preclinical and clinical settings, including recommended dual therapy for BRAFV600E-mutant anaplastic cancers. However, primary or secondary resistance and variable efficacy constrain durable benefit, motivating short-term MAPK inhibitor redifferentiation strategies to restore sodium–iodide symporter expression and enable retreatment with radioactive iodine, supported by recent studies and resistance mechanism analyses.",{"@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/mapk-pathway-inhibitors-in-thyroid-cancer-preclinical-and-clinical-data/385510/",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/mapk-pathway-inhibitors-in-thyroid-cancer-preclinical-and-clinical-data/385510.png","ImageObject",300,407,{"name":42,"@type":43},"anakgang17","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-27","2026-09-24",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",11,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"Why is the MAPK (RAS-RAF-MEK-ERK) pathway important in thyroid cancer?","Question",{"text":63,"@type":64},"The pathway regulates cell proliferation, differentiation, and survival. Overexpression and overactivation are observed in many solid cancers, especially thyroid cancers, making pathway components targets for inhibitory therapies.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What is the role of RAF and MEK inhibitors in thyroid cancer treatment?",{"text":68,"@type":64},"Therapies targeting RAF and MEK have been tested across preclinical and clinical models. In clinical practice, dual BRAF plus MEK inhibition is recommended for anaplastic cancers with the BRAFV600E mutation.",{"name":70,"@type":61,"acceptedAnswer":71},"How do MAPK pathway inhibitors support redifferentiation and retreatment with radioactive iodine?",{"text":72,"@type":64},"A short-term course can evaluate the tumor’s capacity to redifferentiate. If sodium–iodide symporter (NIS) expression is re-induced, patients may be retreated using radioactive iodine therapy.","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},385510,1790464098,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,127],{"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":116,"doc_module":4,"doc_module_name":25,"category_name":117,"show_sort_weight":118,"slug":119},9,"Religion & Spirituality",20,"religion-spirituality",{"id":118,"doc_module":4,"doc_module_name":25,"category_name":121,"show_sort_weight":118,"slug":122},"World Cup","world-cup",{"id":124,"doc_module":4,"doc_module_name":25,"category_name":125,"show_sort_weight":124,"slug":126},10,"Lifestyle","lifestyle",{"id":128,"doc_module":4,"doc_module_name":25,"category_name":129,"show_sort_weight":97,"slug":130},19,"General","general",{"code":4,"msg":82,"data":132},{"doc_id":79,"user_id":133,"nickname":42,"user_avatar":134,"doc_module":4,"category_id":107,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":140,"language":141,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":12,"update_tm":145,"read_time":99},962090883568,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","cancers   \nReview  \nMAPK Pathway Inhibitors in Thyroid Cancer: Preclinical and Clinical Data  \nLouis Schubert 1,2, Mohamed Lamine Mariko 1,2, J²ræme Clerc 3, Olivier Huillard 4 and Lionel Groussin 1,2, *  \nCitation: Schubert, L.; Mariko, M.L.; Clerc, J.; Huillard, O.; Groussin, L. MAPK Pathway Inhibitors in Thyroid Cancer: Preclinical and Clinical Data. Cancers 2023, 15, 710 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cancers15030710  \nAcademic Editor: Vasko Vasyl  \nReceived: 12 December 2022  \nRevised: 15 January 2023  \nAccepted: 17 January 2023  \nPublished: 24 January 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 Endocrinology, Hæpital Cochin, Assistance Publique-Hæpitaux de Paris, 75014 Paris, France  \n2 Institut Cochin, Inserm U1016, CNRS UMR8104, Universit² Paris Cit², 75014 Paris, France  \n3 Department of Nuclear Medicine, Hæpital Cochin, Assistance Publique-Hæpitaux de Paris, Universit² Paris Cit², 75014 Paris, France  \n4 Institut du Cancer Paris CARPEM, Department of Medical Oncology, Hæpital Cochin, Assistance Publique-Hæpitaux de Paris, 75014 Paris, France  \n* Correspondence: [lionel.groussin@aphp.fr](lionel.groussin@aphp.fr)  \nSimple Summary: The Ras-Raf-MEK-ERK signaling pathway is responsible for regulating cell proliferation, differentiation and survival. Overexpression and overactivation of members within the signaling cascade have been observed in many solid cancers and especially in thyroid cancers. These members are therefore the target of inhibitory therapies, for example tyrosine kinase inhibitors or monoclonal antibodies. These drugs are already used in clinical practice, but their efficacy is not always satisfactory, and they could be subject to escape phenomenon. This is the reason why research is focusing on developing new molecules. We aimed to provide an overview of the MAPK pathway's physiologic regulation. Furthermore, we summarized the preclinical and clinical studies including redifferentiation studies that used MAPK pathway inhibitors in thyroid cancers.  \nAbstract: Thyroid cancer is the most common endocrine cancer, with a good prognosis in most cases. However, some cancers of follicular origin are metastatic or recurrent and eventually become radioiodine refractory thyroid cancers (RAIR-TC) . These more aggressive cancers are a clinical concern for which the therapeutic arsenal remains limited. Molecular biology of these tumors has highlighted a hyper-activation of the Mitogen-Activated Protein Kinases (MAPK) pathway (RAS-RAF-MEK-ERK), mostly secondary to the BRAFV600E hotspot mutation occurring in about 60% of papillary cancers and 45% of anaplastic cancers. Therapies targeting the different protagonists of this signaling pathway have been tested in preclinical and clinical models: first and second generation RAF inhibitors and MEK inhibitors. In clinical practice, dual therapies with a BRAF inhibitor and a MEK inhibitor are being recommended in anaplastic cancers with the BRAFV600E mutation. Concerning RAIR-TC, these inhibitors can be used as anti-proliferative drugs, but their efficacy is inconsistent due to primary or secondary resistance. A specific therapeutic approach in thyroid cancers consists of performing a short-term treatment with these MAPK pathway inhibitors to evaluate their capacity to redifferentiate a refractory tumor, with the aim of retreating the patients by radioactive iodine therapy in case of re-expression of the sodium–iodide symporter (NIS) . In this work, we report data from recent preclinical and clinical studies on the efficacy of MAPK pathway inhibitors and their resistance mechanisms. We will also r","cbCaipoEs6Xxj3dX","https://ap.wps.com/l/cbCaipoEs6Xxj3dX","pdf",1561819,24,"English","# Introduction\n## Epidemiology and histological subtypes of thyroid cancer\n# Therapeutic targeting of the MAPK pathway\n## RAS-RAF-MEK-ERK signaling and BRAFV600E-driven hyperactivation\n## RAF inhibitors and MEK inhibitors in preclinical and clinical models\n## Resistance mechanisms and variable efficacy\n## Redifferentiation with MAPK pathway inhibitors to enable radioactive iodine retreatment","[{\"question\":\"Why is the MAPK (RAS-RAF-MEK-ERK) pathway important in thyroid cancer?\",\"answer\":\"The pathway regulates cell proliferation, differentiation, and survival. Overexpression and overactivation are observed in many solid cancers, especially thyroid cancers, making pathway components targets for inhibitory therapies.\"},{\"question\":\"What is the role of RAF and MEK inhibitors in thyroid cancer treatment?\",\"answer\":\"Therapies targeting RAF and MEK have been tested across preclinical and clinical models. In clinical practice, dual BRAF plus MEK inhibition is recommended for anaplastic cancers with the BRAFV600E mutation.\"},{\"question\":\"How do MAPK pathway inhibitors support redifferentiation and retreatment with radioactive iodine?\",\"answer\":\"A short-term course can evaluate the tumor’s capacity to redifferentiate. If sodium–iodide symporter (NIS) expression is re-induced, patients may be retreated using radioactive iodine therapy.\"}]","MAPK Pathway Inhibitors in Thyroid Cancer - Preclinical and Clinical Data | PDF",1790269663]