Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1.
Cell Rep
; 7(4): 999-1008, 2014 May 22.
Article
de En
| MEDLINE
| ID: mdl-24813888
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Adénocarcinome
/
Protocoles de polychimiothérapie antinéoplasique
/
Complexes multiprotéiques
/
Sérine-thréonine kinases TOR
/
Récepteurs ErbB
/
Tumeurs du poumon
Type d'étude:
Clinical_trials
/
Prognostic_studies
/
Risk_factors_studies
Limites:
Animals
/
Humans
Langue:
En
Journal:
Cell Rep
Année:
2014
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique