Cell Reports
Volume 7, Issue 4, 22 May 2014, Pages 999-1008
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Acquired Resistance of EGFR-Mutant Lung Adenocarcinomas to Afatinib plus Cetuximab Is Associated with Activation of mTORC1

https://doi.org/10.1016/j.celrep.2014.04.014Get rights and content
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Highlights

  • mTORC1 activation in EGFR-mutant tumors with resistance to afatinib plus cetuximab

  • Afatinib plus cetuximab-resistant tumors have genomic alterations in NF2 and TSC1

  • NF2 loss and TSC1 loss lead to mTORC1 activation

  • mTOR inhibition resensitizes resistant tumors to afatinib plus cetuximab therapy

Summary

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.

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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Co-first author

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Co-senior author