The role of HER3 on HER2-driven gallbladder carcinogenesis and possible HER2/HER3 targeting therapy by pertuzumab for gallbladder canrcinoma

Abstract

e22083 Background: ErbB2 has been known to be important for gallbladder carcinogenesis. Supporting this, the gene amplification of HER2 was found in ca. 20% of human gallbladder carcinoma (GBC) (Kawamoto, et al. Gastrointest Cancer Res 2007). Following these results, a Phase II study of trastuzumab for treatment of GBC (NSC 688097) is being conducted. Although the mechanism of HER2 activation is not well understood, the role of HER3 in HER2-driven tumorigenesis has been discussed and we have concluded that HER2/HER3 heterodimerization might be important for GBC cell proliferation (ASCOGI 2009, ab#155). In this study, we determined HER family expressions in human GBC and examined the effect of pertuzumab against human GBC cell lines. Methods: Tissues from 47 GBCs and 6 non-cancerous gallbladders were examined. All cases were screened for HER1, HER2, HER3 expressions by immunohistochemistry (IHC) and those HER family gene amplification by fluorescence in situ hybridization (FISH) were performed. 6 human GBC cell lines were also analyzed by Western blotting and FISH as well and their growth assays were investigated with heregulin stimulation to confirm the existence of HER2/HER3 heterodimerization. Then, GBC cells were cultured with heregulin and various doses of pertuzumab for 72 hours and CCK-8 assay was performed. Results: HER3, HER2 and HER1 overexpression by IHC was found in 34%, 32% and 19% of GBCs, respectively. Phosphorylated (p-) HER2 and p-HER1 were found in 23% and 11% of GBCs, respectively. FISH analysis was considered successful in the same serial sections. HER3, HER2 and HER1 FISH (+) was found in 26%, 19% and 4% of GBCs, respectively. Three of 6 GBC cell lines were recognized their growth curves with heregulin were increasing. These 3 cell lines showed good responses to the treatment with pertuzumab. Conclusions: More than 20% of GBC over-expressed either HER2 or HER3. These HER2 and HER3 may form heterodimer, which in turn results in the activation of HER2. The cell lines proliferating with the administration of heregulin showed good responses to the pertuzumab treatment. Therefore, HER2/HER3 heterodimerization may be an ideal biomarker for the treatment by pertuzumab and this agent may be a new therapeutic regimen for GBC. No significant financial relationships to disclose.