PIK3CAH1047R-induced paradoxical ERK activation results in resistance to BRAFV600E specific inhibitors in BRAFV600E PIK3CAH1047R double mutant thyroid tumors

Abstract

Thyroid carcinomas are the most prevalent endocrine cancers. The BRAFV600E mutation is found in 40% of the papillary type and 25% of the anaplastic type. BRAFV600E inhibitors have shown great success in melanoma but, they have been, to date, less successful in thyroid cancer. About 50% of anaplastic thyroid carcinomas present mutations/amplification of the phosphatidylinositol 3' kinase. Here we propose to investigate if the hyper activation of that pathway could influence the response to BRAFV600E specific inhibitors. To test this, we used two mouse models of thyroid cancer. Single mutant (BRAFV600E) mice responded to BRAFV600E-specific inhibition (PLX-4720), while double mutant mice (BRAFV..