Abstract 3443: A new medical tool to discriminate on a radiotherapy concomitant treatment for non-small cell lung cancer patients

Abstract

Abstract 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