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
Introduction: The radioresistance of non-small cell lung cancer cells is a less explored and poorly defined field compared with drug resistance. Our group has previously reported that the loss of IGFBP-3 expression by promoter hypermethylation results in reduced tumor cell sensitivity to cisplatin in NSCLC, however the role of the IGF-I/IGBP-3 axe on radiosensitivity in cancer is controversial because of the differing results when various tumor types are evaluated. The purpose of the present study is to investigate the role of radiotherapy on the biology of IGFBP-3 promoter methylation and its clinical value as a potential tool for deciding on a concomitant radiotherapy after NSCLC surgery. Experimental procedure: In the present study we have worked with 5 human cancer cell lines, 40 NSCLC surgical sample patients with known response to CDDP and radiotherapy treatments and 10 control samples with non neoplastic pathology. We have study the relationship between a dose-response radiotherapy treatment and the IGFBP-3 gene expression regulated by promoter methylation measured by Radiation-clonogenic cell survival assays, RT-PCR, bisulfite modification and quantitative methylation specific PCR. We have also studied, the activation of the IGFIR, ERK and PI3K/AKT pathways through the analysis of the AKT, pAKT, pERK, ERK, pIGFIR and IGFIR protein levels by Western-Blot analysis. Additionally, in order to provide a helpful tool that enables clinicians to identify patients with a potential response to radiotherapy, we have used The TCGA annotation to correlate the IGFBP-3 methylation score of the NSCLC patients with their clinical-pathological parameters. Results: Our results suggest in vitro evidence that linked the presence of an IGFBP-3 unmethylated promoter with poor response to radiation. Radiation might sensitize chemotherapy-resistant cells by reactivating IGFBP-3-expression through promoter demethylation, inactivating the PI3K/AKT pathway. Our translational results indicate that patients harboring an unmethylated promoter could benefit more from a chemotherapy schedule alone than from a multimodality therapy involving radiotherapy and platinum-based treatments, increasing their OS by 2.5 years (p = .03). Conclusion: Our findings indiucate that radiotherapy does not improve survival for patients harboring an unmethylated IGFBP-3 promoter. Citation Format: Maria I. Ibáñez-de-Cáceres, Olga Pernía, Cristobal Belda-Iniesta, Olga Vera, Julia Jimenez, Carlos Rodriguez, Javier Soto, Javier de Castro, Teresa Macias, Federico Rojo, Joan Albanell, Rosario Perona. A new medical tool to discriminate on a radiotherapy concomitant treatment for non-small cell lung cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3443. doi:10.1158/1538-7445.AM2015-3443
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