IGFBP-3 methylation-derived deficiency mediates the resistance to cisplatin through the activation of the IGFIR/Akt pathway in non-small cell lung cancer.
Oncogene
; 32(10): 1274-83, 2013 Mar 07.
Article
em En
| MEDLINE
| ID: mdl-22543588
ABSTRACT
Although many cancers initially respond to cisplatin (CDDP)-based chemotherapy, resistance frequently develops. Insulin-like growth factor-binding protein-3 (IGFBP-3) silencing by promoter methylation is involved in the CDDP-acquired resistance process in non-small cell lung cancer (NSCLC) patients. Our purpose is to design a translational-based profile to predict resistance in NSCLC by studying the role of IGFBP-3 in the phosphatidyl inositol 3-kinase (PI3K) signaling pathway. We have first examined the relationship between IGFBP-3 expression regulated by promoter methylation and activation of the epidermal growth factor receptor (EGFR), insulin-like growth factor-I receptor (IGFIR) and PI3K/AKT pathways in 10 human cancer cell lines and 25 NSCLC patients with known IGFBP-3 methylation status and response to CDDP. Then, to provide a helpful tool that enables clinicians to identify patients with a potential response to CDDP, we have calculated the association between our diagnostic test and the true outcome of analyzed samples in terms of cisplatin IC50; the inhibitory concentration that kills 50% of the cell population. Our results suggest that loss of IGFBP-3 expression by promoter methylation in tumor cells treated with CDDP may activate the PI3K/AKT pathway through the specific derepression of IGFIR signaling, inducing resistance to CDDP. This study also provides a predictive test for clinical practice with an accuracy and precision of 0.84 and 0.9, respectively, (P=0.0062). We present a biomarker test that could provide clinicians with a robust tool with which to decide on the use of CDDP, improving patient clinical outcomes.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cisplatino
/
Receptor IGF Tipo 1
/
Carcinoma Pulmonar de Células não Pequenas
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Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina
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Metilação de DNA
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Proteínas Proto-Oncogênicas c-akt
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Neoplasias Pulmonares
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Oncogene
Assunto da revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Espanha