2. Academic Validation
  3. CRISPR-Based Gene Dependency Screens reveal Mechanism of BRAF Inhibitor Resistance in Anaplastic Thyroid Cancer

CRISPR-Based Gene Dependency Screens reveal Mechanism of BRAF Inhibitor Resistance in Anaplastic Thyroid Cancer

  • bioRxiv. 2025 Jun 27:2025.06.26.661609. doi: 10.1101/2025.06.26.661609.
Shawn Noronha 1 2,  Yue Liu 3,  Gaga Geneti 4,  Haojian Li 2 4,  Xiaolin Wu 5,  David Sun 5,  Vaibhavi Gujar 2,  Takashi Furusawa 2,  Alexei Lobanov 6,  Maggie Cam 6,  Lipika R Pal 7,  Nishanth Nair 7,  Chi-Ping Day 7,  Eytan Ruppin 7,  Chandrayee Gosh 8,  Jiangnan Hu 8,  Suresh Kumar 2,  Thorkell Andresson 9,  King Chan 9,  Maura O'Neill 9,  Raj Chari 10,  Yves Pommier 2,  Jaydira Del Rivero 2,  Urbain Weyemi 2,  Electron Kebebew 8,  Myriem Boufraqech 1
Affiliations

Affiliations

  • 1 Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
  • 2 Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
  • 3 Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 7871.
  • 4 Laboratory Animal Sciences Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
  • 5 NCI Genomics Technology Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research/Frederick, Maryland, USA.
  • 6 Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. Advanced Biomedical Computational Sciences, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, 21701, USA.
  • 7 Cancer Data Science Lab/Center for Cancer Research/National Cancer Institute/National Institutes of Health, Bethesda, MD 20892, USA.
  • 8 Department of Surgery and Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
  • 9 Protein Characterization Laboratory/Cancer Research Technology Program/Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
  • 10 Genome Modification Core, Laboratory Animal Sciences Program, Frederick, Maryland, USA.
PMID: 40667288 DOI: 10.1101/2025.06.26.661609
Abstract

Anaplastic 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 the 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 both in vitro and in vivo. Using gene essentiality score across a large panel of 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.

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