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Cell Rep. 2014 May 22;7(4):999-1008. doi: 10.1016/j.celrep.2014.04.014. Epub 2014 May 9.

Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1.

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  • 1Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 2Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 3Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 4Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 5Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 6Antitumor Assessment Core, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
  • 7Department of Radiology, Michigan State University, East Lansing, MI 48824, USA.
  • 8Program in the Biological and Biomedical Science, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 9Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 10James Thoracic Center, The Ohio State University Medical Center, Columbus, OH 43210, USA.
  • 11Foundation Medicine Inc., Cambridge, MA 02141, USA.
  • 12Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT 06510, USA.
  • 13Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 14Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: katerina.politi@yale.edu.

Abstract

Patients with EGFR-mutant lung adenocarcinomas (LUADs) who initially respond to first-generation tyrosine kinase inhibitors (TKIs) develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. The addition of rapamycin reversed resistance in vivo. Analysis of afatinib-plus-cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling, including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib plus cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs.

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

PMID:
24813888
[PubMed - indexed for MEDLINE]
PMCID:
PMC4074596
[Available on 2015-05-22]
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