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Updated: Sep 15, 2025
Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
CRISPR-Based Gene Dependency Screens reveal Mechanism of BRAF Inhibitor Resistance in Anaplastic Thyroid Cancer
Shawn Noronha1,2, Yue Liu3, Gaga Geneti4
1Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
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.
Insights
TAZ deficiency is synthetically lethal with BRAF inhibitors in anaplastic thyroid cancer (ATC). Targeting TAZ can overcome therapy resistance and enhance cell death in BRAFV600E-driven ATC, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Anaplastic thyroid cancer (ATC) is an aggressive malignancy with limited treatment options.
- Therapy resistance to BRAF inhibitors is a major challenge in treating BRAFV600E-driven ATC.
Purpose of the Study:
- To identify novel therapeutic targets to overcome BRAF inhibitor resistance in ATC.
- To investigate the role of TAZ (WWTR1) in BRAF inhibitor response.
Main Methods:
- Utilized CRISPR/KO and CRISPR/activation screens to identify genes synthetically lethal with BRAF inhibitors.
- Assessed TAZ expression in ATC and its impact on drug sensitivity in vitro and in vivo.
- Analyzed gene essentiality scores across cancer cell lines.
- Investigated the mechanistic link between TAZ, Unfolded Protein Response (UPR), protein synthesis, and ferroptosis.
Main Results:
- TAZ deficiency was found to be synthetically lethal with BRAF inhibitors in ATC.
- TAZ is overexpressed in ATC and its loss enhances sensitivity to BRAF inhibitors.
- BRAFV600E-driven cancers exhibit high sensitivity to TAZ loss.
- TAZ loss represses UPR, reverses protein synthesis inhibition, and promotes ferroptosis in dabrafenib-treated ATC.
Conclusions:
- TAZ is a novel therapeutic target for overcoming BRAF inhibitor resistance in undifferentiated thyroid cancer.
- Targeting TAZ holds promise for improving treatment outcomes in BRAFV600E-driven ATC.
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