Abstract
Abstract Purpose: Many cancers initially respond to Cisplatin-based chemotherapy; however, resistance frequently develops. We have recently reported that reduction of IGFBP-3 expression by promoter methylation is involved in the CDDP acquired resistance process in 3 matched CDDP sensitive/resistant human cancer cell lines and in a human cohort of 36 in non-small cell lung cancer (NSCLC) patients, probably because CDDP also induces DNA methylation de novo. The purpose of the present study is to investigate the role of IGFBP-3 in the PI3K signaling pathway alterations to design a translational based-profile to predict resistance in NSCLC. The biological significance of IGFBP-3 is of great importance in controlling cell growth, transformation and survival; as IGF-I binds to IGFBP-3 with stronger affinity than to its own receptor (IGFIR), blocking their interaction and abolishing the mitogenic and antiapoptotic actions. IGF-I is also able to activate EGF receptor. Those tyrosine kinases receptors (IGFIR and EGFR), signal through the PI3K/Akt pathway, that plays a crucial role in cell growth, proliferation, and survival and is commonly upregulated during tumorigenesis, including NSCLC; although the precise mechanism is not well defined. Patients and methods: In the present study we have examined the relationship between first, IGFBP-3 gene expression regulated by promoter methylation measured by RT-PCR, bisulfite sequencing and methylation specific PCR and second the activation of the EGFR, IGFIR and PI3K/AKT pathways through the analysis of the PTEN, AKT, pAKT, pEGFR, EGFR, pIGFIR and IGFIR protein levels by Western-Blot, immunofluorescence and immunohistochemical analysis in 10 human cancer cell lines and in 25 NSCLC patients with known IGFBP-3 methylation status and response to CDDP. Additionally, in order to provide a helpful tool that enables clinicians to identify or to exclude patients with a potential response to cisplatin, we have used the Fisher's exact test within a 2x2 contingence table to calculate the association between our diagnostic test and the true outcome of analyzed samples in terms of cisplatin IC50. Results: 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). Conclusion: We present a biomarker-test that could provide clinicians with a robust tool with which to decide on the use of cisplatin, improving patient clinical outcomes. Supported by FIS project number: PS09/00472 and a Miguel Servet financial grant to Ibanez de Caceres, I (CP08/000689; PI-717). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1726. doi:1538-7445.AM2012-1726
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