Abstract 1027: EGFR targeting antibody SYM004 causes radiosensitization in tumor cells expressing wild-type K-Ras via modulation of MAPK signaling.

Abstract

Abstract SYM004 is a promising new cancer therapeutic agent containing a mixture of two antibodies that target distinct epitopes on domain III of the EGFR. Treatment of tumor cells with SYM004 leads to clustering of EGFR followed by rapid internalization and degradation. We have recently shown that the combination of SYM004 and radiation therapy (RT) induces potent anti-tumor effects in head and neck (H&N) and lung cancer cell lines. In this study we demonstrate that radiosensitization via SYM004 correlates with inhibition of DNA double strand break repair and induction of apoptosis. These effects are promoted by down regulation of the MAPK pathway. Treatment of SCC6 and H226 cell lines with SYM004 for 30min or 24h prior to irradiation leads to a 1.2 - 1.7 fold increase in unrepaired DNA double strand breaks (DSB) 24h after 2 Gy RT (detected via DNA repair foci formation). The fraction of early (1.8 -1.9 fold) and late (1.3 - 1.7 fold) apoptotic cells increased in both cell lines. However, these effects were reversible by treating the cells with 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of Raf, for 30 min before RT at concentrations as low as 0.1 μM. In addition, mutant K-Ras cells lines A549 and H358 showed no radiosensitization after treatment with SYM004 for 24h prior to RT via DNA repair or apoptosis. Furthermore, transfection of SCC6 cell lines with a K-Ras version carrying an activating SNP (G12V) reversed the inhibitory effect on DNA repair induced by SYM004 in wild type K-Ras cells. These data suggest that the superior impact of combination therapy with SYM004 and RT on wild type K-Ras tumor cell lines reflects alterations in DNA repair and apoptosis via modulation of the MAPK pathway. Citation Format: Jarob Saker, Shyhmin Huang, Lindsey Park, Mikkel Pedersen, Michael Kragh, Paul Harari. EGFR targeting antibody SYM004 causes radiosensitization in tumor cells expressing wild-type K-Ras via modulation of MAPK signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1027. doi:10.1158/1538-7445.AM2013-1027