Resistance to EGFR-TKI can be mediated through multiple signaling pathways converging upon cap-dependent translation in EGFR-wild type NSCLC.
J Thorac Oncol
; 8(9): 1142-7, 2013 Sep.
Article
em En
| MEDLINE
| ID: mdl-23883783
ABSTRACT
INTRODUCTION:
For the majority of patients with non-small-cell lung cancer (NSCLC), response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is suboptimal. In models of acquired resistance to EGFR-TKI, activation of Akt phosphorylation is frequently observed. Because Akt activation results in downstream initiation of cap-dependent protein translation, we hypothesized that a strategy of targeting cap-dependent translation in combination with erlotinib might enhance therapy.METHODS:
NSCLC cells that are wild type for EGFR were assayed for sensitivity to erlotinib. Serum-starved NSCLC cells were assayed for EGFR signaling and downstream pathway activation by immunoblot after stimulation with epidermal growth factor. EGFR signaling and signaling mediators of cap-dependent translation were assayed by immunoblot under serum-replete conditions 24 hours after treatment with erlotinib. Finally, combination treatment with erlotinib and two different cap-dependent translation inhibitors were done to assess the effect on cell viability.RESULTS:
EGFR signaling is coupled to activation of cap-dependent translation in EGFR wild-type cells. Erlotinib inhibits EGFR phosphorylation in EGFR-TKI resistant cells, however, results in activation of downstream signaling molecules including Akt and extracellular regulated kinase, ERK 1/2, resulting in maintenance of eukaryotic initiation factor 4F (eIF4F) activation. eIF4F cap-complex formation is maintained in erlotinib-resistant cells, but not in erlotinib-sensitive cells. Finally, using an antisense oligonucleotide against eukaryotic translation initiation factor 4E and a small-molecule inhibitor to disrupt eIF4F formation, we show that cap-dependent translation inhibition can enhance sensitivity to erlotinib.CONCLUSION:
The results of these studies support further clinical development of translation inhibitors for treatment of NSCLC in combination with erlotinib.
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Base de dados:
MEDLINE
Assunto principal:
Capuzes de RNA
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Transdução de Sinais
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Carcinoma Pulmonar de Células não Pequenas
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Resistencia a Medicamentos Antineoplásicos
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Inibidores de Proteínas Quinases
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Receptores ErbB
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Mutação
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article