PIK3CA(H1047R)-induced paradoxical ERK activation results in resistance to BRAF(V600E) specific inhibitors in BRAF(V600E) PIK3CA(H1047R) double 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 showed 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.