Influence of the HER receptor ligand system on sensitivity to cetuximab and trastuzumab in gastric cancer cell lines

Abstract

PurposeGastric cancer remains a major health concern, and improvement of the therapeutic options is crucial. Treatment with targeted therapeutics such as the EGFR-targeting antibody cetuximab or the HER2-targeting antibody trastuzumab is either ineffective or moderately effective in this disease, respectively. In this study, we analysed the involvement of the HER receptor ligands amphiregulin (AREG), epidermal growth factor (EGF), heparin-binding epidermal growth factor (HB-EGF) and transforming growth factor alpha (TGFα) in the responsiveness of gastric cancer cell lines to cetuximab and trastuzumab.MethodsA panel of 11 gastric cancer cell lines was characterized for cetuximab and trastuzumab sensitivity, ligand secretion and expression and activation of the HER receptors using WST-1 cell proliferation assays, ELISAs and Western blot analyses. We further investigated the effects of an exogenous ligand application on the cetuximab and trastuzumab sensitivity.ResultsWe found no correlation between TGFα secretion and the sensitivity to cetuximab or trastuzumab. For AREG, we confirmed previous results indicating that this ligand is a positive predictor of cetuximab sensitivity. Exogenous HB-EGF was effective in rescuing sensitive cell lines from inhibition of cell proliferation by both, cetuximab and trastuzumab.ConclusionsOur data indicate that HB-EGF may be a useful marker for the prediction of trastuzumab sensitivity in gastric cancer.Electronic supplementary materialThe online version of this article (doi:10.1007/s00432-016-2308-z) contains supplementary material, which is available to authorized users.

Effects of trastuzumab and afatinib on kinase activity in gastric cancer cell lines

“…The effect of trastuzumab and afatinib on the proliferation of NCI‐N87, MKN7, and MKN1 cells was analyzed in an attempt to search for differences in the phenotypic reaction of the cells to the different drugs. The Hs746T cell line was included in the analysis as a control because this cell line is a known trastuzumab nonresponder (Kneissl et al ., ).…”

GC1118, a novel anti-EGFR antibody, has potent KRAS mutation-independent antitumor activity compared with cetuximab in gastric cancer

“…Previous studies have evaluated the effects of cetuximab only in KRAS wild-type cell lines [14,15]. The resistance mechanism to cetuximab shown by many tumor types remains unclear, although KRAS mutation, as well as EGFR mutation and HER2 or MET activation, has been implicated [15][16][17][18][19][20][21][22]. HRAS mutation or upregulated expression of microRNA-100 and microRNA-125b have also been shown to be associated with cetuximab resistance [23,24].…”

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

“…Besides HB-EGF, other ErbB ligands (transforming growth factor-α (TGF-α) and amphiregulin (AREG)) have a prognostic impact on gastric cancer and might make up potential targets in cancer therapy [283][284][285]. Furthermore, trastuzumab sensitivity in gastric cancer can be predicted by HB-EGF expression [286]. Gastric cancer invasion can be increased by nuclear translocation of the cytoplasmic domain of HB-EGF [287,288].…”