PIK3CAH1047R-induced paradoxical ERK activation results in resistance to BRAFV600E specific inhibitors in BRAFV600E PIK3CAH1047R double mutant thyroid tumors.

Rölli, Matthias Andreas; Ruffieux-Daidiée, Dorothée; Stooss, Amandine; El Mokh, Oussama; Phillips, Wayne A; Dettmer, Matthias; Charles, Roch-Philippe (2017). PIK3CAH1047R-induced paradoxical ERK activation results in resistance to BRAFV600E specific inhibitors in BRAFV600E PIK3CAH1047R double mutant thyroid tumors. OncoTarget, 8(61), pp. 103207-103222. Impact Journals LLC 10.18632/oncotarget.21732

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Faculty Institutions > NCCR TransCure
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
04 Faculty of Medicine > Service Sector > Institute of Pathology
09 Interdisciplinary Units > Microscopy Imaging Center (MIC)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Rölli, Matthias Andreas; Ruffieux, Dorothée; Stooss, Amandine; El Mokh, Oussama; Dettmer, Matthias and Charles, Roch-Philippe

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1949-2553

Publisher:

Impact Journals LLC

Funders:

[42] Schweizerischer Nationalfonds
[65] NCCR TransCure

Language:

English

Submitter:

Roch-Philippe Charles

Date Deposited:

09 May 2018 15:10

Last Modified:

22 Oct 2019 16:57

Publisher DOI:

10.18632/oncotarget.21732

PubMed ID:

29262556

Uncontrolled Keywords:

BRAFV600E inhibitor resistance PI3’K inhibitors aggressive thyroid cancer overcoming resistance paradoxical ERK activation

BORIS DOI:

10.7892/boris.109404

URI:

https://boris.unibe.ch/id/eprint/109404

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