Unlocking mechanisms of resistance to targeted therapy in thyroid cancer

Division Of Basic Sciences - Nci

Investigators

Abstract

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 the other metabolic pathways following treatment with BRAF inhibitor