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Published on: December 9, 2015
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, Maryland, USA.
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 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.
Insights
Targeting TAZ (WWTR1) deficiency offers a new strategy against aggressive anaplastic thyroid cancer (ATC). This approach enhances sensitivity to BRAF inhibitors, potentially overcoming therapy resistance and improving patient outcomes in BRAFV600E-driven tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Anaplastic thyroid cancer (ATC) is highly aggressive, with therapy resistance limiting treatment efficacy for BRAFV600E-mutated cases.
- BRAFV600E inhibitors show promise but face challenges due to acquired resistance, necessitating novel therapeutic strategies.
- Understanding resistance mechanisms is crucial for developing effective treatments for undifferentiated thyroid cancer.
Purpose of the Study:
- To identify novel therapeutic targets that synergize with BRAF inhibitors in ATC.
- To investigate the role of TAZ (WWTR1) in regulating sensitivity to BRAF inhibitors in ATC.
- To elucidate the molecular mechanisms underlying TAZ-mediated synthetic lethality with BRAF inhibition.
Main Methods:
- Utilized CRISPR/KO and CRISPR/activation screens to identify genes synthetically lethal with BRAF inhibitors in ATC.
- Assessed TAZ expression levels in ATC and well-differentiated thyroid tumors.
- Performed mechanistic studies involving gene essentiality scores, Unfolded Protein Response (UPR) assays, protein synthesis measurements, and ferroptosis induction.
Main Results:
- TAZ deficiency was identified as synthetically lethal with BRAF inhibitors in ATC.
- TAZ is overexpressed in ATC and its loss enhances sensitivity to BRAF inhibitors, particularly in BRAFV600E-driven cancers.
- TAZ loss represses the Unfolded Protein Response (UPR), reverses protein synthesis inhibition, and promotes ferroptosis in dabrafenib-treated ATC cells.
Conclusions:
- TAZ (WWTR1) is a novel therapeutic target for overcoming BRAF inhibitor resistance in anaplastic thyroid cancer.
- Targeting TAZ in combination with BRAF inhibitors presents a promising strategy for treating aggressive thyroid cancers.
- These findings offer new insights into the molecular mechanisms driving therapeutic resistance in ATC.
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