Abstract 1605: Cetuximab inhibits migration, invasion, metastasis and epithelial-mesenchymal transition but not proliferation via GEP100-Arf6-AMAP1 pathway in head and neck squamous cell carcinoma

Abstract

Abstract Background: Recently, irradiation combined with Cetuximab (Cmab) is being one of the standard therapeutic options against head and neck squamous cell carcinoma (HNSCC), especially in advanced/recurrent cases. While this concurrent chemo-radiotherapy is widely accepted and tolerated, Cmab monotherapy has been reported to be unsatisfactory to treat HNSCC, and detailed mechanism of Cmab to show such clinical efficacy is unknown. Methods: To assess the impact of Cmab on proliferation, migration, and invasion of HNSCC, WST assay, wound healing assay, and matrigel invasion assay were incorporated in this study. Effects of Cmab on the grade of epithelial-mesenchymal transition (EMT), expression level of membrane type 1-matrix-metalloproteinase (MT1-MMP), and activity of EGFR-GEP100-Arf6-AMAP1 pathway, were evaluated using the immunocytochemistry, western blot analysis and Arf6 activation assay, respectively. Furthermore, In vivo efficacy of Cmab was evaluated in highly aggressive and metastatic HSC-3-M3 cells using orthotopic xenograft model in nude mice nu/nu. Results: Inhibition of migration and invasion were observed in 4 HNSCC cell lines by Cmab application. However, proliferation potential of HNSCC were not affected by this chemotherapeutic agent. Increased expression of E-cadherin, with decreased expression of N-cadherin and MT1-MMP, were observed after Cmab treatment in vitro to suggest that Cmab may inhibit EMT in HNSCC. Furthermore, inhibition of Tyr 1086 phosphorylation in EGFR, as well as the inactivation of Arf6 coupled with suppression of both GEP100 and AMAP1 expressions were observed by Cmab application. These results suggested that Cmab might have the potential to suppress the activity of EGFR-GEP100-Arf6-AMAP1 pathway. Furthermore, less metastasis of the cancer was observed in the Cmab treatment group compared with control group in vivo. Conclusions: Our study is the first to provide that Cmab could affect HNSCC through inhibition of migration and invasion of cancer cells, regardless of its anti-proliferative action. EMT inhibition after Cmab application was also clarified in this study. Furthermore, our study suggested that EGFR-GEP100-Arf6-AMAP1 pathway may have some role in the invasion and metastasis of HNSCC. Future studies to further assess the precise mechanism of Cmab against HNSCC are warranted. Citation Format: Yoshifumi Matsumoto, Hiroyuki Sakurai, Yasunao Kogashiwa, Koichiro Saito. Cetuximab inhibits migration, invasion, metastasis and epithelial-mesenchymal transition but not proliferation via GEP100-Arf6-AMAP1 pathway in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1605.