PIK3CAH1047R-induced paradoxical ERK activation results in resistance to BRAFV600Especific inhibitors in BRAFV600EPIK3CAH1047Rdouble mutant thyroid tumors

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 could show that this resistance was concomitant to a paradoxical activation of the MAP-Kinase pathway, which could be overturned by phosphoinositide 3-kinase inhibition in vivo in our mouse model and in vitro 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.