Noronha Shawn, Liu Yue, Geneti Gaga, Li Haojian, Wu Xiaolin, Sun David, Gujar Vaibhavi, Furusawa Takashi, Lobanov Alexei, Cam Maggie, Pal Lipika R, Nair Nishanth, Day Chi-Ping, Ruppin Eytan, Gosh Chandrayee, Hu Jiangnan, Kumar Suresh, Andresson Thorkell, Chan King, O'Neill Maura, Chari Raj, Pommier Yves, Del Rivero Jaydira, Weyemi Urbain, Kebebew Electron, Boufraqech Myriem
Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
bioRxiv. 2025 Jun 27:2025.06.26.661609. doi: 10.1101/2025.06.26.661609.
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 and . 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.
间变性甲状腺癌（ATC）是甲状腺癌中侵袭性最强的形式。尽管最近在治疗BRAFV600E驱动的ATC方面取得了进展，但治疗耐药性仍然是一个重大挑战，常常导致疾病进展和死亡。我们利用一个针对BRAFV600E抑制剂治疗反应量身定制的聚焦CRISPR/基因敲除筛选与一个CRISPR/激活筛选并行，确定了TAZ（由WWTR1基因编码）缺陷在ATC中与BRAF抑制剂具有合成致死性。与分化良好的甲状腺肿瘤相比，TAZ在ATC中过表达。我们证明，TAZ缺陷的ATC细胞在体外和体内对BRAF抑制剂均表现出更高的敏感性。通过对大量癌细胞系进行基因必需性评分，我们发现BRAFV600E驱动的癌症对TAZ缺失高度敏感，这与野生型BRAF和非BRAFV600E的癌症不同。从机制上讲，我们证明达拉非尼在ER应激下触发未折叠蛋白反应（UPR）并抑制蛋白质合成。TAZ缺失抑制UPR，逆转对蛋白质合成的抑制，并在达拉非尼治疗的ATC中通过铁死亡触发细胞死亡增加。总的来说，我们的研究结果揭示了TAZ是克服未分化甲状腺癌对BRAF抑制剂耐药性的新靶点。
