Abstract 1866: HER3 targeting sensitizes HNSCC to cetuximab - evidence from cell line and patient derived xenograft (PDX) models

Abstract

Abstract Background and Objectives: Our previous study demonstrated that a combination of EGFR-targeted antibody cetuximab and HER3-specific antibody MM121 could significantly inhibit growth of head and neck squamous cell carcinoma (HNSCC) as compared with either of the single drugs. The current study aims to understand the role of HER3 in cetuximab resistance and the anti-tumor mechanisms of dual targeting of EGFR/HER3 in HNSCC. Materials and Methods: A cetuximab resistant HNSCC cell line SCC1-C, its parental cell line SCC1-P, and a HER3 knockdown counterpart SCC1-C/H were treated with cetuximab, MM121 and their combination. SRB and colony formation assays were performed to investigate the combined effect of MM121 and cetuximab on cancer cell growth. Activations of EGFR, HER2, HER3, AKT, and ERK signaling pathways were evaluated by Western blotting. The SCC1-C xenograft animal model and PDX models from 6 patients with HNSCC were utilized to determine the combined efficacy of MM121 and cetuximab. Results: Cetuximab induced HER3 activation and HER2/HER3 dimerization in HNSCC cell lines. The combined treatment blocked both EGFR and HER3 activation and inhibited both PI3K/AKT and ERK signaling pathways as well as HNSCC cell growth more effectively compared to either single antibody treatment in vitro. Furthermore, knock down of HER3 re-sensitized the resistant cell line to cetuximab. The anti-HER3/EGFR combination also demonstrated better efficacy than either single agent antibody in the cetuximab resistant HNSCC xenograft model and the PDX animal models. In PDX models from patients 1-4, both cetuximab and the combination significantly inhibited tumor growth in nude mice compare to the control (p<0.001 for both treatments) and there was no difference between single cetuximab and the combination. In 1 of the 4 PDXs, tumors treated with cetuximab grew back while no relapse could be detected in the combination group. In the PDX from patient 5, only the combination treatment significantly inhibited tumor growth (p<0.004) which was also more effective than cetuximab treatment (p<0.032). In the PDX from patient 6, both cetuximab and the combination significantly inhibited tumor growth in nude mice as compared with the control (p<0.001 for both treatments). However, the combination was significantly more effective than either of the single agents (p<0.0004 and p<0.003, respectively). Conclusion: Our study indicates that dual targeting of EGFR and HER3 is more effective than cetuximab alone in both cetuximab resistant HNSCC cell line and PDX models. These results pave the way for further clinical investigations using multiple targeting strategies in patients who have failed cetuximab based therapy. (The current study is supported by NIH grant R21 CA182661 to NFS and ZGC). Citation Format: Dongsheng Wang, Guoqing Qian, hongzheng zhang, kelly R. Magliocca, sreenivas nannapaneni, zhengjia chen, mihir R. patel, Mark W. El-Deiry, J.trad Wadsworth, dong M. Shin, fadlo R. khuri, Nabil F. Saba, Zhuo G. chen. HER3 targeting sensitizes HNSCC to cetuximab - evidence from cell line and patient derived xenograft (PDX) models. [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 1866.