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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 volume 32, pages 1274–1283 (2013)Cite this article

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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.

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Abbreviations

ATCC:

American Type Culture Collection

BS:

bisulfite sequencing

CDDP:

cisplatin

DFS:

disease-free survival

ECACC:

European Collection of Cell Cultures

EGFR:

epidermal growth factor receptor

IGFBP-3 :

insulin-like growth factor-binding protein-3

IGFIR:

insulin-like growth factor-I receptor

MSP:

methylation-specific PCR

NSCLC:

non-small cell lung cancer.

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Acknowledgements

We thank J Siegfried for the English correction, F Dominguez for her technical help, the Health Investigation Funding to IIC through the ‘Miguel Servet’ program (CP08/000689; PI-717) and acknowledge the support of PI08/1485 and PS09/00472 and PI11/00949 projects. We thank MINECO for its support through SAF2010-19230 Grant. This work was supported by FIS PI08-1485, FIS 11-00949, PS09/00472 and Miguel Servet financial support to Ibanez de Caceres, I (CP 08/000689; PI-717).

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Authors and Affiliations

  1. Instituto de Investigaciones Biomedicas CSIC/UAM, CIBER de Enfermedades Raras (CIBERER), Madrid, Spain

    M Cortés-Sempere & R Perona

  2. Biomarkers and Experimental Therapeutics in Cancer. IdiPAZ, Madrid, Spain

    M Cortés-Sempere, O Pernía, C Rodriguez, J de Castro Carpeño, C Belda-Iniesta, R Perona & I Ibanez de Caceres

  3. Laboratory of Cellular Engineering, La Paz University Hospital. IdiPAZ, Madrid, Spain

    M P de Miguel

  4. Cancer Epigenetics Laboratory, INGEMM, La Paz University Hospital, Madrid, Spain

    O Pernía, C Rodriguez & I Ibanez de Caceres

  5. Department of Pathology, La Paz University Hospital, Madrid, Spain

    M Nistal

  6. Department of Pathology, Madrid Norte Sanchinarro University Hospital, Madrid, Spain

    E Conde & F López-Ríos

  7. Department of Medical Oncology, Madrid Norte Sanchinarro University Hospital, Madrid, Spain

    C Belda-Iniesta

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Correspondence to R Perona or I Ibanez de Caceres.

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Cortés-Sempere, M., de Miguel, M., Pernía, O. et al. 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, 1274–1283 (2013). https://doi.org/10.1038/onc.2012.146

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