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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.

Author information

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

PMID:
24813888
PMCID:
PMC4074596
DOI:
10.1016/j.celrep.2014.04.014
[Indexed for MEDLINE]
Free PMC Article

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