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 (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 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 BRAFV600E specific inhibitors in a clinically relevant mouse model of thyroid cancer.
Highlights
Thyroid cancer is the most frequent form of endocrine malignancy
BRAFV600E single mutant thyroid tumor respond to PLX4720 inhibition, while BRAFV600E; PIK3CAH1047R double mutant tumors do not
The BRAFV600E mutation is detected in many cancer types such as melanoma, colon, ovarian, lung and prostate cancers [37, 38]
Summary
Papillary thyroid cancer (PTC) is the most prevalent type of thyroid carcinoma (80%). It is moderately aggressive, moderately lymphometastatic and has a response rate above 90% to standard radioiodine treatment. The main risk is a possible progression (5– 10% of the cases) to more aggressive variants including radio-iodine-resistant PTC, poorly differentiated thyroid carcinoma and anaplastic thyroid carcinoma (ATC) [1]. Unlike most cancer patients, ATC patients do not predominantly succumb to “dissemination” of the disease, but rather to local invasion of the tumor into the tracheal space. There is currently no efficient treatment for ATC, the disease being highly resistant to radio- and chemotherapies, including radioiodine I131 that usually www.impactjournals.com/oncotarget yields excellent therapeutic outcome in other thyroid cancers
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
