Abstract 1636: ErbB4 is a new therapeutic target for metastasis and anoikis resistance in Ewing's sarcoma

Abstract

Abstract Most Ewing sarcoma (ES)-related deaths occur as a result of metastatic disease. As a barrier to metastases, cells normally undergo a form of cell death called ‘‘anoikis” after they lose contact with the extracellular matrix or neighboring cells. Tumor cells that acquire malignant potential develop mechanisms to suppress anoikis. We previously demonstrated that ES tumors suppress anoikis and show prolonged survival as multicellular spheroids, which mimic micrometastases under anchorage-independent conditions. Here we have used the paired CHLA-9 primary tumor line established at diagnosis and the metastatic CHLA-10 line established from the same patient after four cycles of induction chemotherapy with cisplatin, doxorubicin, cyclophosphamide, and etoposide, as well as high-throughput Affymetrix whole exon array platforms to screen for potential therapeutic targets to treat metastatic disease. We have identified ErbB4, a member of the epidermal growth factor receptor (EGFR) family, as a novel mediator of anoikis resistance in ES. We detected a 4-fold increase in ERBB4, along with enhanced ErbB4 protein expression and Tyr kinase activation (confirmed by P-Tyr kinase proteome arrays) in CHLA-10 cells grown under anchorage independent conditions, compared to CHLA-9 tumor cells under the same conditions. Upregulated ErbB4 expression was further confirmed in a panel of metastatic vs. primary ES cell lines at both the mRNA and protein levels. We are currently validating these findings in the clinical setting by analyzing ErbB4 expression in paired primary vs. metastatic biopsies from ES patients. shRNA-mediated knockdown of ErbB4, or treatment with the ErbB inhibitor Lapatinib, dramatically reduced proliferation, decelerated tumor invasion, and sensitized metastatic/chemoresistant ES tumors to chemotherapeutic drugs used to treat ES patients. Taken together, our findings identify ErbB4 as a novel target for metastasis and anoikis resistance in ES. 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 1636. doi:10.1158/1538-7445.AM2011-1636