Use of novel radiosensitizers and radiation-specific miRNAs to modulate radiation response in non-small cell lung adenocarcinoma (NSCLC).

Abstract

e17519 Background: Tumor response to radiotherapy in NSCLC remains markedly heterogeneous. Few successful radiosensitivity predictive assays exist that can be applied to individualize radiotherapeutic options. Methods: Using Bayesian regression analysis, a 52-gene expression signature that predicts sensitivity to external beam radiotherapy was developed and independently validated. On the basis of the signature, using Connectivity Map, novel candidate radiosensitizers were identified and tested in vitro by cell proliferation assays on predicted radioresistant NSCLC cell lines at three different radiation doses (3, 5 and 7 Gy). Cisplatin was used as a clinically relevant control. Furthermore, a systemic computational approach was developed to identify potential radiation-specific miRNAs, which were later transiently expressed and validated in vitro using the aforementioned NSCLC cell lines. Results: The 52-gene expression signature accurately predicted radiosensitivity in vitro and in individuals treated with radiation or chemoradiation independent of tissue. Tumor cell-specific novel agents, such as ethacrynic acid and docosahexaenoic acid have shown to radiosensitize NSCLC cell lines in a drug and radiation dose-indepependent manner. Finally, radiation-specific miRNAs (hsa-let-7b, hsa- let-7i and hsa-miR30a), which were shown to regulate RAS signaling pathway as evidenced from Western analyses, significantly radiosensitize (p<0.001 for all three miRNAs with respect to mock transfected controls) NSCLC cell lines. Conclusions: Comprehensive genomic analysis using gene expression signatures and miRNA data provides opportunities to better understand the mechanisms underlying radiation response and provides novel therapeutic opportunities in NSCLC. No significant financial relationships to disclose.