Abstract 2129: HB-EGF expression in gastric cancer promotes chemotherapy resistance and represents a promising target for molecular therapy and a novel biomarker of 5-FU resistance

Abstract

Abstract The incidence of gastric cancer (GC) has been on the decline in the U.S. over the last 40 years, but remains high in Asia and Latin America. The primary treatment for early-stage GC is surgery. Many patients will also benefit from adjuvant 5-fluorouracil (5-FU) or platin-based chemotherapy. When it presents at an advanced stage, GC uniformly carries a poor prognosis, due to chemotherapy resistance. To improve the response of GC to chemotherapy, molecular-targeted therapies are needed. One of the EGFR family ligands called heparin-binding epidermal growth factor (HB-EGF) was recently found to be up-regulated in several epithelial-based malignancies, including GC. Our objective in this study was to evaluate the role of HB-EGF in GC chemotherapy resistance. We hypothesize that constitutive expression of HB-EGF is associated with chemotherapy resistance. Furthermore we propose that inhibition of HB-EGF enhances drug sensitivity and augments the apoptotic response to chemotherapy in GC. To test our hypothesis, we isolated RNA and protein from a panel of 6 GC cell lines and measured the basal HB-EGF expression compared to that of normal gastric epithelia. We similarly measured HB-EGF expression in response to 5-FU or cisplatin treatment, and then determined the response when cells were co-treated with HB-EGF or an inhibitor of HB-EGF (CRM197). We found that HB-EGF expression at both the protein and RNA levels was highly variable across the panel of GC cell lines. In addition, HB-EGF expression increased in response to drug treatment at 24 and 48 hours post-treatment. A positive correlation was observed between HB-EGF mRNA levels and chemoresistance to 5-FU. GC cell lines that are high-expressers of HB-EGF showed decreased cell growth when treated with CRM197, whereas low-expressers increased when treated with recombinant HB-EGF. The combination of CRM197 with anticancer agents increased apoptosis in high-expressers, but made no significant difference in low-expressers. Likewise, HB-EGF gene silencing using a lentiviral short-hairpin RNA significantly decreased high-expressers survival and proliferation. Similar to our findings using GC cell lines, we found that human gastric cancer tumor samples showed highly variable HB-EGF expression compared to their matching normal gastric epithelia. Our findings suggest that HB-EGF plays an important role in the proliferation and chemotherapy resistance of a subset of gastric cancers. HB-EGF may represent a promising molecular target in those select patients, in whom the gastric cancer expresses high levels of HB-EGF. Furthermore, HB-EGF expression may represent a novel biomarker for 5-FU chemoresistance in patients with gastric cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2129. doi:10.1158/1538-7445.AM2011-2129