Acquired resistance of EGFR-mutant lung Adenocarcinomas to Afatinib plus Cetuximab is associated with activation of mTORC1

Valentina Pirazzoli, Caroline Nebhan, Xiaoling Song, Anna Wurtz, Zenta Walther, Guoping Cai, Zhongming Zhao, Peilin Jia, Elisa de Stanchina, Erik M. Shapiro, Molly Gale, Ruonan Yin, Leora Horn, David P. Carbone, Philip J. Stephens, Vincent Miller, Scott Gettinger, William Pao, Katerina Politi

Research output: Contribution to journalArticle

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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.

LanguageEnglish (US)
Pages999-1008
Number of pages10
JournalCell Reports
Volume7
Issue number4
DOIs
StatePublished - May 22 2014

Profile

Protein-Tyrosine Kinases
Chemical activation
Drug Resistance
Biopsy
Drug Combinations
Sirolimus
Pharmaceutical Preparations
Genes
Antibodies
BIBW 2992
mechanistic target of rapamycin complex 1
Cetuximab
Adenocarcinoma of lung
Therapeutics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Pirazzoli, V., Nebhan, C., Song, X., Wurtz, A., Walther, Z., Cai, G., ... Politi, K. (2014). Acquired resistance of EGFR-mutant lung Adenocarcinomas to Afatinib plus Cetuximab is associated with activation of mTORC1. Cell Reports, 7(4), 999-1008. DOI: 10.1016/j.celrep.2014.04.014

Acquired resistance of EGFR-mutant lung Adenocarcinomas to Afatinib plus Cetuximab is associated with activation of mTORC1. / Pirazzoli, Valentina; Nebhan, Caroline; Song, Xiaoling; Wurtz, Anna; Walther, Zenta; Cai, Guoping; Zhao, Zhongming; Jia, Peilin; de Stanchina, Elisa; Shapiro, Erik M.; Gale, Molly; Yin, Ruonan; Horn, Leora; Carbone, David P.; Stephens, Philip J.; Miller, Vincent; Gettinger, Scott; Pao, William; Politi, Katerina.

In: Cell Reports, Vol. 7, No. 4, 22.05.2014, p. 999-1008.

Research output: Contribution to journalArticle

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 2014, 'Acquired resistance of EGFR-mutant lung Adenocarcinomas to Afatinib plus Cetuximab is associated with activation of mTORC1' Cell Reports, vol 7, no. 4, pp. 999-1008. DOI: 10.1016/j.celrep.2014.04.014
Pirazzoli V, Nebhan C, Song X, Wurtz A, Walther Z, Cai G et al. Acquired resistance of EGFR-mutant lung Adenocarcinomas to Afatinib plus Cetuximab is associated with activation of mTORC1. Cell Reports. 2014 May 22;7(4):999-1008. Available from, DOI: 10.1016/j.celrep.2014.04.014
Pirazzoli, Valentina ; Nebhan, Caroline ; Song, Xiaoling ; Wurtz, Anna ; Walther, Zenta ; Cai, Guoping ; Zhao, Zhongming ; Jia, Peilin ; de Stanchina, Elisa ; Shapiro, Erik M. ; Gale, Molly ; Yin, Ruonan ; Horn, Leora ; Carbone, David P. ; Stephens, Philip J. ; Miller, Vincent ; Gettinger, Scott ; Pao, William ; Politi, Katerina. / Acquired resistance of EGFR-mutant lung Adenocarcinomas to Afatinib plus Cetuximab is associated with activation of mTORC1. In: Cell Reports. 2014 ; Vol. 7, No. 4. pp. 999-1008
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