Abstract C44: Targeting neuregulin1-ErbB3 signaling in wild-type BRAF/NRAS melanoma.

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Abstract Melanoma is the deadliest form of skin cancer due to its highly metastatic nature and refractoriness to standard chemotherapies. At present, few therapy options exist for wild-type BRAF/NRAS (WT/WT) melanoma patients. We examined the role of the neuregulin (NRG1)-ErbB3 signaling pathway in WT/WT melanoma cells since it is emerging as an important player in melanocyte homeostasis and melanoma pathogenesis. NRG1 has been shown to promote melanoblast proliferation and survival. ErbB3 is elevated in malignant melanoma specimens and cell lines and its expression correlates with reduced patient survival. The purpose of this study was to determine the role of the NRG1-ErbB3 signaling pathway in WT/WT melanoma cells. We demonstrated that in a subgroup of WT/WT cell lines, expressing high level of ErbB3 and NRG1, neuregulin is able to activate ErbB3 in basal conditions. Knockdown of NRG1 in high NRG1-expressing cells led to reduction of cell viability. This effect was associated with a decrease in the phosphorylation of ErbB3 and ErbB2 receptors as well as downstream AKT and ERK1/2 signaling. All these effects were rescued by exogenous addition of NRG1. We obtained analogous effects targeting ErbB3 with either small interfering RNAs or with clinical grade ErbB3 monoclonal antibodies. In these WT/WT cell lines with high expression of NRG1, inhibition of ErbB2-ErbB3 dimerization with pertuzumab caused a decrease in AKT phosphorylation and cell growth, indicating that ErbB3 signaling is dependent on ErbB2. Synergistic effects on cell growth as well as on AKT and ERK1/2 signaling were observed targeting ErbB2 and ErbB3 combining both antibodies. Our study demonstrates that targeting ErbB3 and ErbB2 signaling in a cohort WT/WT melanoma cell lines leads to tumor growth reduction. We propose that NRG1 activation of ErbB3 signaling promotes progression in these tumors and that these findings may form the basis for the use of agents targeting the NRG1-ErbB3 axis as novel treatment strategies in a subset of malignant melanoma. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C44. Citation Format: Claudia Capparelli, Nadège Gaborit, Yosef Yarden, Andrew Aplin. Targeting neuregulin1-ErbB3 signaling in wild-type BRAF/NRAS melanoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C44.