Characterization of EGFR family gene aberrations in cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) is a highly lethal malignancy of the biliary tract with very few treatment options. Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER2) have been considered as potential therapeutic targets in CCA. In the present study, we attempted to clarify the clinicopathological significance of all EGFR family members, EGFR, HER2, HER3 and HER4, across the full spectrum of CCAs. Immunohistochemistry and FISH were performed to validate expressions and genetic aberrations of these molecules retrospectively in 175 CCA patients. EGFR, HER3 and HER4 were overexpressed in 20 (30.8%), 8 (12.3%) and 41 (63.1%) of the 65 intrahepatic cholangiocarcinomas (IHCCs), and in 23 (20.9%), 13 (11.8%) and 62 (56.4%) of the 110 extrahepatic cholangiocarcinomas (EHCCs), respectively. Overexpression of HER2 was exclusively identified in EHCCs, among which the rate was 4.5% (5/110). A significant association was identified between EGFR amplification and EGFR overexpression (P=0.002). Similarly, HER2 amplification was strongly associated with HER2 overexpression (P<0.001). Multivariate analysis suggested that EGFR overexpression is an independent prognostic factor in IHCC, but not in EHCC cases [HR (95% CI): 3.689 (1.253-10.587), P=0.018]. Notably, for the first time, we demonstrated HER4 expression is a prognostic factor in EGFR-negative IHCC patients. In vitro data further suggested a tumor-suppressor role of HER4 in CCA. siRNA knockdown of HER4 significantly increased RBE cell migration and invasion. By contrast, HER4 overexpression decreased proliferation of HuCCT-1 cells and their migratory and invasive capacity. In summary, our results revealed expression of the EGFR family members in CCA development and progression. CCAs differentially express HER2 protein based on tumor location. HER4 expression status allows stratification of CCA patients into different survival categories.

HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?

“…All four studies had a HQ HER3 expression assessment (Table 3). The pooled mean overall HER3 overexpression rate was 27.9 % (95 % CI 9.7–46.1 %) [51, 76, 81, 83]; only one study reported HER3 amplification rate (26.5 %) [83] (Table 2). …”

“…All of the four studies with HER3 expression data had HER2 expression data available for correlation analysis [51, 76, 81, 83]. No statistically significant correlation was identified between HER2 and HER3 overexpression (four studies; Spearman rho = 0.2; p value 0.8) (Fig.…”

Multi-OMIC profiling of survival and metabolic signaling networks in cells subjected to photodynamic therapy

“…Finally, ZnPC distributes to multiple intracellular loci after uptake of the liposomes [17, 18], from which different cell death pathways but also cell survival pathways are activated [2]. In preliminary experiments it was discovered that epidermal growth factor receptor (EGFR), a receptor overexpressed in a multitude of cancers [19] including perihilar cholangiocarcinoma [20, 21], was afflicted by PDT with ZnPC-liposomes. EGFR constitutes an important druggable target in cancer therapy, as evidenced by the approval status of the monoclonal antibodies cetuximab and panitumumab, as well as the kinase inhibitors gefitinib and erlotinib [22].…”

ERBB4 Expression in Ovarian Serous Carcinoma Resistant to Platinum-Based Therapy

“…By contrast, mutations of ERBB4 have also been associated with multiple cancer types. 16,17 Therefore, to identify a possible role of ERBB4 in the development of platinum resistance, we sought to study ERBB4 expression by immunohistochemistry in clinical samples obtained from patients with complete response (CR) and incomplete response (IR) to platinum-based chemotherapy and ovarian cancer cell lines.…”