Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer.
Br J Cancer
; 117(12): 1777-1786, 2017 Dec 05.
Article
em En
| MEDLINE
| ID: mdl-29123263
ABSTRACT
BACKGROUND:
Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving.METHODS:
We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation.RESULTS:
Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R.CONCLUSIONS:
Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
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Protocolos de Quimioterapia Combinada Antineoplásica
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Núcleo Celular
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Receptor IGF Tipo 1
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Resistencia a Medicamentos Antineoplásicos
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Transporte Proteico
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Revista:
Br J Cancer
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Espanha