Abstract 2612: ljm716, an anti her3 antibody that inhibits her3 dimerization, displays anti-tumor activity in esophageal squamous cell cancer

Abstract

Abstract Background: Esophageal cancer is the eighth most common cancer and the sixth most common cause of cancer related death in the world. Squamous cell carcinoma is the predominant histologic subtype of esophageal cancer, particularly in Asia. Currently, no targeted therapy has been approved for treating this type of disease. Platinum-based combination chemotherapy remains to be the standard care for first line treatment of advanced or metastatic esophageal cancer with limited efficacy. Activation of EGFR/HER3/PI3K pathway is frequently observed in esophageal cancer, however, their therapeutic value remains to be further tested. Methods: In this study, we evaluated the anti-tumor activity of LJM716, a fully human anti-HER3 antibody, either alone or in combination with anti-EGFR antibody cetuximab or PI3K alpha subunit inhibitor BYL719 in esophageal squamous cancer. LJM716, cetuximab and BYL719 single agent as well as their pair-wised combination activity were assessed in 24 esophageal squamous cancer cell (ESCC) lines using the CellTiter-Glo® Luminescent Cell Viability Assay. Single agent and combination anti-tumor activities of these reagents were also tested in selected cell line xenograft and patient derived xenograft mouse models. Results: NRG1 expression (60%), PIK3CA mutation (8%), moderate PIK3CA (30%) and EGFR (30%) amplification were detected in a panel of 24 ESCC lines. Anti-HER3 antibody LJM716 potently inhibited HER3 phosphorylation and decreased pAKT level in these cell lines. In vitro, LJM716 inhibited proliferation of a sub-set of ESCC lines. LJM716 further enhanced and broadened the anti-tumor activities of both BYL719 and cetuximab in ESCC lines. In mouse xenograft models, LJM716 single agent treatment induced tumor stasis while combination with either BYL719 or cetuximab induced model dependent tumor regression. Conclusion: NRG1-HER3-PI3K pathway activation is commonly observed in esophageal squamous cell cancer. Activation of HER3 is a potential mechanism leading to resistance to EGFR or PI3K targeted therapies, and combining anti-HER3 therapies with therapies targeting PI3K/EGFR may provide new therapeutic strategy for patients with esophageal squamous cell cancer. Citation Format: Qing Sheng, Hui-Qin Wang, rita das, yan chen, jinsheng liang, Fiona Xu, zongyao Wang, Z. Alexander Cao, youzhen Wang, alan huang. ljm716, an anti her3 antibody that inhibits her3 dimerization, displays anti-tumor activity in esophageal squamous cell cancer. [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 2612. doi:10.1158/1538-7445.AM2014-2612