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

Pirazzoli V, Nebhan C, Song X, Wurtz A, Walther Z, Cai G, Zhao Z, Jia P, de Stanchina E, Shapiro EM, Gale M, Yin R, Horn L, Carbone DP, Stephens PJ, Miller V, Gettinger S, Pao W, Politi K
Cell Rep. 2014 7 (4): 999-1008

PMID: 24813888 · PMCID: PMC4074596 · DOI:10.1016/j.celrep.2014.04.014

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.

MeSH Terms (22)

Adenocarcinoma Adenocarcinoma of Lung Afatinib Animals Antibodies, Monoclonal, Humanized Antineoplastic Combined Chemotherapy Protocols Cell Line, Tumor Cetuximab Drug Resistance, Neoplasm ErbB Receptors Humans Lung Neoplasms Mechanistic Target of Rapamycin Complex 1 Mice Mice, Nude Mice, Transgenic Multiprotein Complexes Mutation Quinazolines Random Allocation TOR Serine-Threonine Kinases Xenograft Model Antitumor Assays

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