Simultaneous ß1 integrin-EGFR targeting and radiosensitization of human head and neck cancer.
J Natl Cancer Inst
; 107(2)2015 Feb.
Article
em En
| MEDLINE
| ID: mdl-25663685
ABSTRACT
BACKGROUND:
Signaling from integrins and receptor tyrosine kinases (RTKs) contributes substantially to therapy resistance of malignant tumors. We investigated simultaneous ß1 integrin-epidermal growth factor receptor (EGFR) targeting plus radiotherapy in human head and neck squamous cell carcinomas (HNSCCs).METHODS:
Ten HNSCC cell lines were grown in three-dimensional laminin-rich extracellular matrix cell cultures and two of them as tumor xenografts in nude mice (n = 12-16 per group). Targeting of ß1 integrin and EGFR with monoclonal inhibitory antibodies (AIIB2 and cetuximab, respectively) was combined with x-ray irradiation. Clonogenic survival, tumor growth, and tumor control (evaluated by Kaplan-Meier analysis), apoptosis, phosphoproteome (interactome, network betweeness centrality analysis), receptor expression (immunohistochemistry), and downstream signaling (western blotting) were assessed. Various mutants of the integrin signaling mediator focal adhesion kinase (FAK) were employed for mechanistic studies. All statistical tests were two-sided.RESULTS:
Compared with ß1 integrin or EGFR single inhibition, combined ß1 integrin-EGFR targeting resulted in enhanced cytotoxicity and radiosensitization in eight out of 10 tested HNSCC cell lines, which responded with an FAK dephosphorylation after ß1 integrin inhibition. In vivo, simultaneous anti-ß1 integrin/anti-EGFR treatment and radiotherapy of UTSCC15 responder xenografts enabled better tumor control compared with anti-EGFR monotherapy and irradiation (hazard ratio [HR] = 6.9, 95% confidence interval [CI] = 1.6 to 30.9, P = .01), in contrast to the SAS nonresponder tumor model (HR = 0.9, 95% CI = 0.4 to 2.3, P = .83). Mechanistically, a protein complex consisting of FAK- and Erk1-mediated prosurvival signals for radiation resistance, which was effectively compromised by ß1 integrin and EGFR blocking.CONCLUSIONS:
Concomitant targeting of ß1 integrin and EGFR seems a powerful and promising approach to overcome radioresistance of HNSCCs.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Carcinoma de Células Escamosas
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Protocolos de Quimioterapia Combinada Antineoplásica
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Integrina beta1
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Terapia de Alvo Molecular
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Receptores ErbB
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Neoplasias de Cabeça e Pescoço
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Anticorpos Monoclonais
Tipo de estudo:
Etiology_studies
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Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Natl Cancer Inst
Ano de publicação:
2015
Tipo de documento:
Article
País de publicação:
EEUU
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ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA