Abstract 4495: Sym013, novel pan-HER monoclonal antibody mixture, augments radiation response in human lung and head and neck tumors

Abstract

Abstract Sym013 represents a novel HER family targeting approach consisting of a mixture of six monoclonal antibodies against EGFR, HER2, and HER3. Sym013 effectively induces rapid, simultaneous down-regulation of all HER members. Compared with single receptor or dual receptor targeting of the HER family, Sym013 provides broader inhibition and greater down-regulation efficacy. In this current study, we examined the capacity of Sym013 in combination with ionizing radiation to augment tumor response in lung (NSCLC) and head and neck (HNSCC) cancer model systems. The anti-proliferative effects of Sym013 were confirmed showing 30-60% growth inhibition across a variety of NSCLC and H&N cancer cell lines that express EGFR, HER2, and/or HER3. Furthermore, Sym013 inhibited the growth of tumor cells that exhibit resistance to cetuximab. Western blot analysis showed a dose-dependent down-regulation of HER family members and downstream MAPK and AKT signaling pathways following 24-hour treatment with Sym013. Clonogenic survival analysis revealed that Sym013 enhanced radiosensitivity in tumor cells following radiation exposure. We characterized the DNA damage profile following radiation via flow cytometric analysis of phosphorylated histone 2AX (γH2AX) foci. This revealed a significant increase of γH2AX following treatment with Sym013 and 2 Gy radiation when compared with Sym013 or radiation alone. Furthermore, combined treatment of Sym013 and radiation induced a significant G1 and G2 arrest. Using Annexin V/PI staining, we also found a significant increase in the apoptotic cell population following treatment of Sym013 and 6 Gy radiation. These results suggest that Sym013 augments radiation response via the induction of cell cycle arrest followed by the induction of apoptosis and cell death, likely reflecting inhibitory effects on DNA damage repair. Additional studies to examine the impact of Sym013 to augment radiation response as well as overcome acquired resistance to cetuximab in xenograft models are in progress. Overall, these data suggest the significant capacity of Sym013 to augment radiation response in lung and head and neck cancers. This unique antibody mixture warrants additional investigation as a promising novel HER family targeting strategy in cancer therapy. Citation Format: David Francis, Shyhmin Huang, Lauryn Werner, Johan Lantto, Ivan D. Horak, Michael Kragh, Paul M. Harari. Sym013, novel pan-HER monoclonal antibody mixture, augments radiation response in human lung and head and neck tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4495. doi:10.1158/1538-7445.AM2014-4495