Award
NIH Reporter #1ZIABC012150-03
Unlocking mechanisms of resistance to targeted therapy in thyroid cancer
Recipient
DIVISION OF BASIC SCIENCES - NCI, UNITED STATES
Award Amount
$429,350.00
Ceiling
$429,350.00
Awarded
April 27, 2024
Identifier
1ZIABC012150-03
This award funds research to identify genetic and metabolic mechanisms of resistance to BRAF inhibitor therapy in advanced thyroid cancer, using CRISPR screening and validation studies.
Description
Our major goal is to identify new determinants of resistance to targeted therapy and more specifically to BRAF inhibitors in advanced and metastatic thyroid cancer. Our overall hypothesis is that BRAFV600E driven-ATC cells heavily rely on certain genes or key pathways to survive canonical treatments targeting oncogenic BRAF. We have performed a CRISPR knockout (KO) and activation screen using a focused library. This screen has identified a gene exhibiting synthetic lethality in anaplastic thyroid carcinoma (ATC) in response to treatment with a BRAF V600E inhibitor. Our findings have been validated both in vivo and in vitro. Currently, we are investigating the metabolic vulnerabilities that drive resistance to BRAF inhibition in anaplastic thyroid cancer. The observed genetic susceptibility to oxidative phosphorylation (OxPhos) in BRAF-mutant tumors prompted us to explore the role of other metabolic pathways following treatment with BRAF inhibitor.