PIK3CAH1047R-induced paradoxical ERK activation results in resistance to BRAFV600E specific inhibitors in BRAFV600E PIK3CAH1047R double mutant thyroid tumors
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Matthias A. Roelli1, Dorothée Ruffieux-Daidié1, Amandine Stooss1, Oussama ElMokh1, Wayne A. Phillips3, Matthias S. Dettmer2 and Roch-Philippe Charles1
1Institut für Biochemie und Molekulare Medizin, Universität Bern, Bern, Switzerland
2Institut für Pathologie, Universität Bern, Bern, Switzerland
3Cancer Biology Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia
Roch-Philippe Charles, email: [email protected]
Keywords: aggressive thyroid cancer, BRAFV600E inhibitor resistance, PI3’K inhibitors, paradoxical ERK activation, overcoming resistance
Received: January 17, 2017 Accepted: September 23, 2017 Published: October 11, 2017
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.
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