RT Journal Article
SR Electronic
T1 PIK3CA<sup>H1047R</sup>-induced paradoxical ERK activation results in resistance to BRAF<sup>V600E</sup> specific inhibitors in BRAF<sup>V600E</sup> PIK3CA<sup>H1047R</sup> double mutant thyroid tumors
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 164533
DO 10.1101/164533
A1 Matthias A. Roelli
A1 Dorothée Ruffieux-Daidié
A1 Amandine Stooss
A1 Oussama ElMokh
A1 Wayne A. Phillips
A1 Matthias S. Dettmer
A1 Roch-Philippe Charles
YR 2017
UL http://biorxiv.org/content/early/2017/07/18/164533.abstract
AB 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 (BRAFV600E; PIK3CAH1047R) 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 BRAFV600E specific inhibitors in a clinically relevant mouse model of thyroid cancer.