ABSTRACT
The methylation status of the IGFBP-3 gene is strongly associated with cisplatin sensitivity in patients with non-small cell lung cancer (NSCLC). In this study, we found in vitro evidence that linked the presence of an unmethylated promoter with poor response to radiation. Our data also indicate that radiation might sensitize chemotherapy-resistant cells by reactivating IGFBP-3-expression through promoter demethylation, inactivating the PI3K/AKT pathway. We also explored the IGFBP-3 methylation effect on overall survival (OS) in a population of 40 NSCLC patients who received adjuvant therapy after R0 surgery. Our 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 y (p = .03). Our findings discard this epi-marker as a prognostic factor in a patient population without adjuvant therapy, indicating that radiotherapy does not improve survival for patients harboring an unmethylated IGFBP-3 promoter.
Subject(s)
Carcinoma, Non-Small-Cell Lung/radiotherapy , Insulin-Like Growth Factor Binding Protein 3/metabolism , Lung Neoplasms/radiotherapy , Promoter Regions, Genetic , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/surgery , Cell Line, Tumor/radiation effects , Cell Survival/genetics , Cell Survival/radiation effects , Combined Modality Therapy , DNA Methylation , Female , Humans , Insulin-Like Growth Factor Binding Protein 3/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Lung Neoplasms/surgery , Male , Middle Aged , Phosphorylation/drug effects , Prognosis , Proto-Oncogene Proteins c-akt/metabolism , Survival Analysis , Treatment OutcomeABSTRACT
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