Abstract 4891: Radiation enhances the efficacy of Bcl-2 and Bcl-XL inhibition in small cell lung cancer: A new concept of using radiation for targeted therapy through contextual oncogene addiction

Abstract

Abstract Purpose: Radiotherapy has a critical role in the treatment of small cell lung cancer (SCLC). Effectiveness of radiation in SCLC remains limited as resistance results from defects in apoptosis. Experimental Design: We investigated whether using a new Bcl-2/Bcl-XL inhibitor, S44563, can enhance radiosensitivity of SCLC cells in vitro and in vivo. We also explored the mechanisms of the potential interaction. Results: In vitro studies confirmed that S44563 induce apoptosis in SCLC cells by inducing hallmarks of apoptosis (cleaved caspase-3, sub-G1 fraction induction and induction of the mitochondrial caspase activation pathway). S44563 markedly enhanced sensitivity of H146 and H69 cells to radiation in clonogenic assay. In vitro experiments demonstrated a greater induction of apoptosis (sub-G1 fraction and cleaved caspase-3) with the combination as well as in vivo caspase-3 immunostaining. This positive interaction between S44563 and radiation was greater when S44563 was given during and after the completion of the radiation, which was explained by the radiation-induced over expression of anti-apoptotic proteins (Bcl-2 and Bcl-XL). in vitro studies based on gene expression and immunoblotting indicated that radiation activates NF-κB pathways which results in anti-apoptotic expression. In addition, S44563 combined with cisplatin-based chemo-radiation showed a dramatic tumor growth delay and increased overall survival in mouse xenograft models.Conclusion: This study underlines the critical role of sequence administration of targeted therapies with conventional therapies such as radiation and chemotherapy. SCLC cells which survive to IR highly rely on the induction of anti apoptotic proteins for their survival therefore yielding to the concept of “contextual oncogene addiction” to the Bcl-2/Bcl-XL pathway. These results suggest that radioresistance results in part from resistance to apoptosis in SCLC mediated by up regulation of Bcl-2/Bcl-XL. The inhibition of Bcl-2 and Bcl-XL leads to the induction of radiation-induced apoptosis and enhances radiation therapy both in vitro and in SCLC xenograft models. Our data suggest that targeting radiation induced survival pathways may constitute an efficient strategy to potentiate IR. 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 4891. doi:1538-7445.AM2012-4891