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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / enzymology
  • Adenocarcinoma of Lung
  • Afatinib
  • Animals
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Cell Line, Tumor
  • Cetuximab
  • Drug Resistance, Neoplasm
  • ErbB Receptors / genetics*
  • ErbB Receptors / metabolism
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • Multiprotein Complexes / metabolism*
  • Mutation
  • Quinazolines / administration & dosage
  • Random Allocation
  • TOR Serine-Threonine Kinases / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal, Humanized
  • Multiprotein Complexes
  • Quinazolines
  • Afatinib
  • TOR Serine-Threonine Kinases
  • EGFR protein, human
  • ErbB Receptors
  • Mechanistic Target of Rapamycin Complex 1
  • Cetuximab

Associated data

  • SRA/SRP040807