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 BRAF^V600E mutation is found in 40% of the papillary type and 25% of the anaplastic type. BRAF^V600E 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 BRAF^V600E specific inhibitors. To test this, we used two mouse models of thyroid cancer. Single mutant (BRAF^V600E) mice responded to BRAF^V600E-specific inhibition (PLX-4720), while double mutant mice (BRAF^V600E; PIK3CA^H1047R) showed resistance and even signs of aggravation. This resistance was abrogated by combination with a phosphoinositide 3-kinase inhibitor. At the molecular level, we showed that this resistance was concomitant to a paradoxical activation of the MAP-Kinase pathway, which could be overturned by phosphoinositide 3-kinase inhibition <i>in vivo</i> in our mouse model and <i>in vitro</i> in human double mutant cell lines. In conclusion, we reveal a phosphoinositide 3-kinase driven, paradoxical MAP-Kinase pathway activation as mechanism for resistance to BRAF^V600E specific inhibitors in a clinically relevant mouse model of thyroid cancer.