Abstract A52: Extracellular matrix regulation of ErbB3 in a subset of wild-type BRAF/NRAS melanoma

While the incidence of melanoma increases each year, treatment options for melanoma patients wild-type for both BRAF and NRAS (WT-WT) remain limited. The tumor microenvironment has been highly implicated in the promotion of tumor growth and proliferation; however, its precise role in melanoma is not well understood. Extracellular matrix (ECM) proteins within the tumor microenvironment have been shown to regulate many cellular pathways, including the activation of several growth factor receptors. The receptor ErbB3 is involved in the regulation of melanocyte homeostasis, and elevated ErbB3 expression in malignant melanomas correlates with reduced patient survival. In our study we demonstrate that, in a subgroup of WT-WT cells, an interaction between melanoma cells and ECM proteins within the tumor microenvironment promotes the activation of the NRG1/ErbB3 pathway, leading to phosphorylation of the downstream target AKT and increased cell growth. Furthermore, knockdown of NRG1 reduced cell viability, which was associated with decreased phosphorylation of ErbB3, its co-receptor ErbB2 and AKT. Analogous effects were obtained targeting ErbB3 with either small interfering RNAs or the neutralizing ErbB3 monoclonal antibodies, huHER-8 and NG33. Additionally, pertuzumab-mediated inhibition of ErbB2 heterodimerization decreased AKT phosphorylation, cell growth in vitro and xenograft growth in vivo. These findings are supportive of the crucial role of the ECM in regulating tumor growth through the activation of ErbB3 signaling, and establish a basis for targeting the NRG1-ErbB3-ErbB2 axis as a novel treatment strategy in a subset of malignant cutaneous melanoma. Citation Format: Sheera Rosenbaum, Claudia Capparelli, Lisa D. Berman-Booty, Nadege Gaborit, Tingting Zhan, Michael A. Davies, Yulius Y. Setiady, Yosef Yarden, Andrew E. Aplin. Extracellular matrix regulation of ErbB3 in a subset of wild-type BRAF/NRAS melanoma. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A52.