Antibody Targeting GRP78 Enhances the Efficacy of Radiation Therapy in Human Glioblastoma and Non-Small Cell Lung Cancer Cell Lines and Tumor Models.

Abstract

<b>Purpose:</b> Non-small cell lung cancer (NSCLC) and glioblastoma multiforme (GBM) have poor median survival. NSCLC and GBM overexpress glucose regulated protein 78 (GRP78), which has a role in radioresistance and recurrence. In this study, we determined the effect of anti-GRP78 antibody and the combined effect of the anti-GRP78 antibody with ionizing radiation (XRT) on NSCLC and GBM cell lines both <i>in vitro</i> and <i>in vivo</i><b>Experimental Design:</b> NSCLC and GBM cancer cell lines were treated with anti-GRP78 antibodies and evaluated for proliferation, colony formation, cell death, and PI3K/Akt/mTOR signaling. The efficacy of anti-GRP78 antibodies on tumor growth in combination with XRT was determined <i>in vivo</i> in mouse xenograft models.<b>Results:</b> GBM and NSCLC cells treated with anti-GRP78 antibodies showed attenuated cell proliferation, colony formation, and enhanced apoptosis. GBM and NSCLC cells treated with anti-GRP78 antibodies also showed global suppression of PI3K/Akt/mTOR signaling. Combining antibody with XRT resulted in significant tumor growth delay in both NSCLC and GBM heterotopic tumor models.<b>Conclusions:</b> Antibodies targeting GRP78 exhibited antitumor activity and enhanced the efficacy of radiation in NSCLC and GBM both <i>in vitro</i> and <i>in vivo</i> GRP78 is a promising novel target, and anti-GRP78 antibodies could be used as an effective cancer therapy alone or in combination with XRT. <i>Clin Cancer Res; 23(10); 2556-64. ©2016 AACR</i>.