Abstract 1684: The potential role of HER3 on HER2-driven biliary carcinogenesis and the possibility for targeted therapy with pertuzumab

Abstract

HER2 has been implicated in biliary carcinogenesis, because gene amplification of HER2 has been observed in 20% of gallbladder carcinoma (GBC) (Kawamoto, et al. GCR 2007). The first-in-class HER2 dimerization inhibitor (HDI) pertuzumab is a humanized monoclonal antibody that binds HER2 at an epitope that prevents HER2 from dimerizing with ligand-activated HER family receptors, In this study, we determined the expression of HER family proteins in GBC, cholangiocellular carcinoma(CC), and examined whether treatment with pertuzumab would affect GBC and CC cell lines. Methods: HER family expression was examined in surgical or biopsied specimens from 47 GBCs and 57 CCs by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Using 6 GBC and 8 CC cell lines, heregulin-stimulated cell proliferation and its inhibition by pertuzumab, were tested in vitro by MTT assay. The phosphorylated HER family proteins and their respective downstream molecules were examined by Western blot analysis. Anti-tumor activity of pertuzumab in vivo was evaluated in the CC cell line KMCH-1 xenograft model with weekly intraperitoneal administration. Results: Over-expression of HER2 or HER3 was observed in 14-34% of all patients (Table 1). Six of 14 cell lines demonstrated over-expression of both HER2 and HER3, and heregulin stimulation increased the proliferation in 3 of them. In the HER2- and HER3- over-expressing KMCH-1, pertuzumab significantly inhibited cell proliferation in a dose-dependent manner. Pertuzumab completely blocked heregulin-induced phosphorylation of HER3. Furthermore, suppression of downstream pathway molecules including pAKT and pS6 were observed. The xenograft model also revealed tumor growth inhibition with pertuzumab. Conclusions: Pertuzumab demonstrated significant antitumor activities in HER2 and HER3 over-expressing cancer cells. Thus, pertuzumab may provide a new therapy option for both HER2- and HER3- positive GBC and CC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1684. doi:1538-7445.AM2012-1684