Acquired resistance of EGFR-mutant lung Adenocarcinomas to Afatinib plus Cetuximab is associated with activation of mTORC1 Journal Article
| Authors: | Pirazzoli, V.; Nebhan, C.; Song, X.; Wurtz, A.; Walther, Z.; Cai, G.; Zhao, Z.; Jia, P.; de Stanchina, E.; Shapiro, E. M.; Gale, M.; Yin, R.; Horn, L.; Carbone, D. P.; Stephens, P. J.; Miller, V.; Gettinger, S.; Pao, W.; Politi, K. |
| Article Title: | Acquired resistance of EGFR-mutant lung Adenocarcinomas to Afatinib plus Cetuximab is associated with activation of mTORC1 |
| 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. © 2014 The Authors. |
| Keywords: | controlled study; protein phosphorylation; treatment response; gene mutation; human cell; nonhuman; nuclear magnetic resonance imaging; animal cell; mouse; phenotype; vasculotropin receptor; animal experiment; animal model; in vivo study; cetuximab; protein tyrosine kinase inhibitor; lung adenocarcinoma; genetic engineering; xenograft; heterozygosity loss; rapamycin; thyroid transcription factor 1; afatinib; human; priority journal; article |
| Journal Title: | Cell Reports |
| Volume: | 7 |
| Issue: | 4 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2014-05-22 |
| Start Page: | 999 |
| End Page: | 1008 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2014.04.014 |
| PROVIDER: | scopus |
| PMCID: | PMC4074596 |
| PUBMED: | 24813888 |
| DOI/URL: | |
| Notes: | Cell Rep. -- Export Date: 8 July 2014 -- Source: Scopus |
