[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-349317-105":59,"doc-detail-349317-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","crispr-based-gene-dependency-screens-reveal-mechanism-of-braf-inhibitor-resistance-in-anaplastic-thyroid-cancer-abstract","CRISPR-Based Gene Dependency Screens Reveal Mechanism of BRAF Inhibitor Resistance in Anaplastic Thyroid Cancer - Abstract","","Anaplastic thyroid cancer (ATC) is highly aggressive, and resistance to targeted BRAFV600E therapy continues to drive progression and death. Using focused CRISPR/KO and CRISPR/activation screens tailored to response to BRAFV600E inhibitor treatment, the study identifies TAZ (WWTR1) deficiency as synthetically lethal with BRAF inhibition in ATC. TAZ is overexpressed in ATC and TAZ loss increases sensitivity to BRAF inhibitors. Mechanistically, dabrafenib induces ER-stress–linked Unfolded Protein Response, suppressing protein synthesis; TAZ loss represses the UPR, restores protein synthesis inhibition, and promotes ferroptosis-driven cell death, revealing a new resistance-overcoming target.",{"@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/crispr-based-gene-dependency-screens-reveal-mechanism-of-braf-inhibitor-resistance-in-anaplastic-thyroid-cancer-abstract/349317/",{"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/crispr-based-gene-dependency-screens-reveal-mechanism-of-braf-inhibitor-resistance-in-anaplastic-thyroid-cancer-abstract/349317.png","ImageObject",300,407,{"name":92,"@type":93},"Mimi","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-23","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":81},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is resistance to BRAFV600E-targeted therapy a major issue in anaplastic thyroid cancer?","Question",{"text":112,"@type":113},"Even with advances for BRAFV600E-driven ATC, many patients develop resistance that leads to disease progression and metastasis.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What did the CRISPR/KO and CRISPR/activation screens identify in ATC?",{"text":117,"@type":113},"The screens identified TAZ (encoded by WWTR1) deficiency as synthetically lethal with BRAF inhibitor treatment in anaplastic thyroid cancer.",{"name":119,"@type":110,"acceptedAnswer":120},"How does TAZ loss influence the response to dabrafenib at the mechanistic level?",{"text":121,"@type":113},"Dabrafenib triggers ER stress and the Unfolded Protein Response while suppressing protein synthesis; TAZ loss represses the UPR, reverses inhibition of protein synthesis, and increases cell death by ferroptosis in treated ATC cells.","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},349317,1790106900,{"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":81,"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},2336477974920,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Molecular Carcinogenesis   \nRESEARCH ARTICLE   \nCRISPR‐Based Gene Dependency Screens Reveal Mechanism of BRAF Inhibitor Resistance in Anaplastic Thyroid Cancer  \nShawn Noronha1,2 | Yue Liu3 | Gaga Geneti4 | Haojian Li2 | Xiaolin Wu5 | David Sun5 | Vaibhavi Gujar2 |  \nTakashi Furusawa2 | Alexei Lobanov6,7 | Maggie Cam6,7 | Lipika R. Pal8 | Nishanth U. Nair8,9 | Chi‐Ping Day8 |  \nEytan Ruppin8 | Chandrayee Ghosh10 | Jiangnan Hu10 | Bhavishya Ramamoorthy1 | Suresh Kumar2 | Thorkell Andresson11 | King Chan11 | Maura O'Neill11 | Raj Chari12 | Yves Pommier2 | Jaydira Del Rivero2 | Urbain Weyemi2 |  \nElectron Kebebew10 | Myriem Boufraqech1   \n1Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA | 2Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA | 3Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA | 4Laboratory Animal Sciences Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA | 5NCI Genomics Technology, Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research/Frederick, Maryland, USA | 6Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA | 7Advanced Biomedical Computational Sciences, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA | 8Cancer Data Science Lab/Center for Cancer Research/National Cancer Institute/National Institutes of Health, Bethesda, Maryland, USA | 9Jim and Eleanor Randall Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA | 10Department of Surgery and Stanford Cancer Institute, Stanford University, Stanford, California, USA | 11Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA | 12Genome Modification Core, Laboratory Animal Sciences Program, Frederick National Lab for Cancer Research, Frederick, Maryland, USA  \nCorrespondence: Myriem Boufraqech ([myriem.boufraqech@nih.gov](myriem.boufraqech@nih.gov))  \nReceived: 25 March 2026 | Revised: 25 March 2026 | Accepted: 3 April 2026  \nABSTRACT  \nAnaplastic thyroid cancer (ATC) is the most aggressive form of thyroid cancer. Despite recent advances in treating BRAFV600E‐driven ATC, therapy resistance remains a significant challenge, often resulting in disease progression and death. Leveraging a focused CRISPR/KO screen in parallel with a CRISPR/activation screen, both tailored on response to BRAFV600E inhibitor treatment, we identified TAZ (encoded by WWTR1 gene) deficiency as synthetically lethal with BRAF inhibitor in ATC. TAZ is overexpressed in ATC compared to well‐differentiated thyroid tumors. We demonstrate that TAZ‐deficient ATC cells display heightened sensitivity to BRAF inhibitors. Using gene essentiality score across cancer cell lines, we found that BRAFV600E‐driven cancers are highly sensitive to TAZ loss, unlike their counterparts with wild‐type BRAF and non‐ BRAFV600E. Mechanistically, we demonstrate that dabrafenib triggers the Unfolded Protein Response (UPR) under ER stress and suppresses protein synthesis. TAZ loss represses the UPR, reverses the inhibition of protein synthesis, and triggers increased cell death by ferroptosis in dabrafenib‐treated ATC. Collectively, our findings unveil TAZ as a new target to overcome resistance to BRAF inhibitors in undifferentiated thyroid cancer.  \n1 | Introduction  \nAnaplastic thyroid cancer (ATC) is a rare yet highly aggressive form of thyroid cancer, comprising less than 2% of all thyroid  \nmalignancies. Distinguished by its rapid progression, early metastasis, and poor prognosis, ATC poses significant clinical challenges, with a 1‐year survival rate of just 39% . Despite its ra","cbCaickiLBztmsbp","https://ap.wps.com/l/cbCaickiLBztmsbp","pdf",4934856,14,"English","# Introduction\n## ATC clinical burden and treatment challenge\n## Focused CRISPR libraries and screening strategy","[{\"question\":\"Why is resistance to BRAFV600E-targeted therapy a major issue in anaplastic thyroid cancer?\",\"answer\":\"Even with advances for BRAFV600E-driven ATC, many patients develop resistance that leads to disease progression and metastasis.\"},{\"question\":\"What did the CRISPR/KO and CRISPR/activation screens identify in ATC?\",\"answer\":\"The screens identified TAZ (encoded by WWTR1) deficiency as synthetically lethal with BRAF inhibitor treatment in anaplastic thyroid cancer.\"},{\"question\":\"How does TAZ loss influence the response to dabrafenib at the mechanistic level?\",\"answer\":\"Dabrafenib triggers ER stress and the Unfolded Protein Response while suppressing protein synthesis; TAZ loss represses the UPR, reverses inhibition of protein synthesis, and increases cell death by ferroptosis in treated ATC cells.\"}]","CRISPR-Based Gene Dependency Screens Reveal Mechanism of BRAF Inhibitor Resistance in Anaplastic Thyroid Cancer - Abstract | PDF",1790082737,35]