Abstract 4110: Combinatory approaches targeting EGFR, HER2 and c-MET in recurrent SCCHN

Abstract

Abstract Squamous cell carcinoma of the head and neck (SCCHN) cells that escape cetuximab inhibition exhibit HER2, HER3, and/or c-Met activation. Simultaneous inhibition of EGFR, HER2, HER3 and c-Met presents an attractive clinical strategy for treating SCCHN that has progresses despite EGFR-targeted therapy. In an effort to develop new combination drug therapy options for recurrent SCCHN, we evaluated three different c-Met inhibitors in combination with a pan-HER inhibitor (afatinib/crizotinib, afatinib/tivantinib, afatinib/cabozantinib) and investigated their anti-tumoral effects. SCCHN cell lines (JHU022 highly expresses c-Met, and SCC1-C is cetuximab resistant) as well as patient derived xenograft (PDX) animal models from patients with recurrent SCCHN were investigated. In our cell line study, western-blot assay indicated that activation of EGFR, HER2, and c-Met was blocked in all three combinations. In addition the downstream PI3K/AKT and ERK signaling pathways were inhibited. Sulforhodamin B colorimetric assay (SRB) revealed SCCHN cell growth was more effectively inhibited by the combinations compared to any of the single inhibitors in vitro. Furthermore, the combination was more potent in inducing apoptosis when compared to each of the single treatments. Finally in the PDX study, all treatment groups had significantly greater efficacy compared to the non-treated control group (p<0.005) and all combination treatments exhibited better efficacy in tumor growth inhibition than their respective single inhibitors (p<0.0l). In conclusion, our study demonstrates that targeting EGFR, HER2, and c-Met with combination of their inhibitors is more effective than each of the single inhibitors alone both in vitro and in SCCHN PDX models. This study paves the way for further clinical investigation of this combination in patients with SCCHN who have progressed after cetuximab-based therapy. (This study is supported by NIH/NCI R21 CA182662-01A1 to NFS and ZGC) Citation Format: Dongsheng Wang, Kelly R. Magliocca, Sreenivas Nannapaneni, Coner Steuer, Mihir R. Patel, Mark W. El-Deiry, Xu Wang, Zhengjia Chen, Dong M. Shin, Nabil F. Saba, Zhuo G. Chen. Combinatory approaches targeting EGFR, HER2 and c-MET in recurrent SCCHN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4110. doi:10.1158/1538-7445.AM2017-4110