Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

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

Matthias A. Roelli, Dorothée Ruffieux-Daidié, Amandine Stooss, Oussama ElMokh, Wayne A. Phillips, Matthias S. Dettmer, View ORCID ProfileRoch-Philippe Charles
doi: https://doi.org/10.1101/164533
Matthias A. Roelli
1Institut für Biochemie und Molekulare Medizin, Universität Bern, Bern, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dorothée Ruffieux-Daidié
1Institut für Biochemie und Molekulare Medizin, Universität Bern, Bern, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Amandine Stooss
1Institut für Biochemie und Molekulare Medizin, Universität Bern, Bern, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Oussama ElMokh
1Institut für Biochemie und Molekulare Medizin, Universität Bern, Bern, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wayne A. Phillips
3Cancer Biology Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthias S. Dettmer
2Institut für Pathologie, Universität Bern, Bern, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Roch-Philippe Charles
1Institut für Biochemie und Molekulare Medizin, Universität Bern, Bern, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Roch-Philippe Charles
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

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 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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
Back to top
PreviousNext
Posted July 18, 2017.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
PIK3CAH1047R-induced paradoxical ERK activation results in resistance to BRAFV600E specific inhibitors in BRAFV600E PIK3CAH1047R double mutant thyroid tumors
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
PIK3CAH1047R-induced paradoxical ERK activation results in resistance to BRAFV600E specific inhibitors in BRAFV600E PIK3CAH1047R double mutant thyroid tumors
Matthias A. Roelli, Dorothée Ruffieux-Daidié, Amandine Stooss, Oussama ElMokh, Wayne A. Phillips, Matthias S. Dettmer, Roch-Philippe Charles
bioRxiv 164533; doi: https://doi.org/10.1101/164533
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
PIK3CAH1047R-induced paradoxical ERK activation results in resistance to BRAFV600E specific inhibitors in BRAFV600E PIK3CAH1047R double mutant thyroid tumors
Matthias A. Roelli, Dorothée Ruffieux-Daidié, Amandine Stooss, Oussama ElMokh, Wayne A. Phillips, Matthias S. Dettmer, Roch-Philippe Charles
bioRxiv 164533; doi: https://doi.org/10.1101/164533

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Cancer Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3514)
  • Biochemistry (7364)
  • Bioengineering (5341)
  • Bioinformatics (20316)
  • Biophysics (10038)
  • Cancer Biology (7771)
  • Cell Biology (11346)
  • Clinical Trials (138)
  • Developmental Biology (6446)
  • Ecology (9978)
  • Epidemiology (2065)
  • Evolutionary Biology (13352)
  • Genetics (9369)
  • Genomics (12603)
  • Immunology (7724)
  • Microbiology (19083)
  • Molecular Biology (7458)
  • Neuroscience (41125)
  • Paleontology (300)
  • Pathology (1235)
  • Pharmacology and Toxicology (2142)
  • Physiology (3174)
  • Plant Biology (6874)
  • Scientific Communication and Education (1276)
  • Synthetic Biology (1900)
  • Systems Biology (5324)
  • Zoology (1091)