Abstract 4435: Targeting Met signaling to overcome human cancer cell resistance to radiation.

Purpose: Targeting signaling pathways that are implicated in cancer cell resistance to therapy are being investigated to improve therapy outcome. One of the receptor tyrosine kinases, c-Met (Met) is frequently overexpressed in many cancer types including non small cell lung cancers (NSCLCs) and head and neck squamous cell carcinomas (HNSCCs) and is associated with resistance to radiation. EMD1214063 is a small molecule inhibitor that suppresses the kinase activity of Met. The current study investigated the potential of EMD1214063 (provided by EMD Serono Merck Inc) in enhancing cancer cell sensitivity to radiation. Materials and Methods: Three NSCLC lines (A549, H460 and H1993) and three HNSCC lines (FaDu, HN-5 and UMSCC-1) with different levels of Met protein were used for the study. The effects of EMD1214063 on Met expression, cell viability, migration and cell radiosensitivity were assessed. Various scheduling effect on the magnitude of increased cell radiosensitivity was evaluated. 53BP1 foci formation was assayed for DNA repair kinetics. In vivo tumor growth delay assays on two NSCLCs and two HNSCCs generated in mice were performed to test the efficacy of EMD1214063 on tumor growth and tumor response to radiation. Results: NSCLC lines expressed higher levels of Met than HNSCC lines. EMD1214063 reduced survival of NSCLC lines markedly and had a minimal effect on HNSCC lines in vitro. Western blots showed three major Met protein bands with molecular weights of about 145 kDa, 60 kDa and 45 kDa. Radiation increased the expression levels of the 145 kDa and 60 kDa fragments of Met in a dose dependent manner. EMD1214063 suppressed the radiation-induced expression of Met and prolonged the presence of 53BP1 foci. It potently enhanced the radiosensitivity of A549, H1993, HN-5 and FaDu but not that of H460 and UMSCC-1. The enhancement factors at the survival fraction of 0.5 ranged from 1.11 to 2.24, with H1993 being the most responsive cell line. In vivo data showed lack of single agent activity of EMD1214063 on the growth of tumor xenografts tested (A549, H460 and FaDu). However, it showed a schedule dependent effect in enhancing A549 tumor xenograft response to radiation: a marked enhancement was observed only when EMD1214063 was given concurrently with fractionated doses of radiation. In vivo studies on other tumor types are ongoing. Conclusions: This study demonstrated that EMD1214063 reduced viability and migration of NSCLC cells and it selectively enhanced radiosensitivity of cells that express higher levels of basal or induced Met and the underlying mechanism may be inhibition of DNA repair. In vivo study data showed EMD1214063 induced a schedule dependent enhancement of tumor response to radiation in a NSCLC line. These data warrant further in vivo investigations aiming at taking best regimens to the clinic testing. This study is being supported by EMD Serono Merck via an independent medical grant. Citation Format: Uma Raju, David P. Molkentine, Jessica M. Molkentine, David N. Valdecanas, K Kian Ang. Targeting Met signaling to overcome human cancer cell resistance to radiation. [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 4435. doi:10.1158/1538-7445.AM2013-4435