ErbB3-ErbB2 Complexes as a Therapeutic Target in a Subset of Wild-type BRAF/NRAS Cutaneous Melanomas

• Published in: Cancer research (Chicago, Ill.) Vol. 75; no. 17; pp. 3554 - 3567
• Main Authors: Capparelli, Claudia, Rosenbaum, Sheera, Berman-Booty, Lisa D, Salhi, Amel, Gaborit, Nadège, Zhan, Tingting, Chervoneva, Inna, Roszik, Jason, Woodman, Scott E, Davies, Michael A, Setiady, Yulius Y, Osman, Iman, Yarden, Yosef, Aplin, Andrew E
• Format: Journal Article
• Language: English
• Published: United States 01-09-2015
• Subjects: Antibodies, Monoclonal, Humanized - administration & dosage; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - genetics; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; GTP Phosphohydrolases - genetics; Humans; MAP Kinase Signaling System - drug effects; Melanoma - drug therapy; Melanoma - genetics; Melanoma - pathology; Melanoma, Cutaneous Malignant; Membrane Proteins - genetics; Molecular Targeted Therapy; Neuregulin-1 - antagonists & inhibitors; Neuregulin-1 - genetics; Proto-Oncogene Proteins B-raf - genetics; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Receptor, ErbB-3 - genetics; Receptor, ErbB-3 - metabolism; Skin Neoplasms
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-14-2959

The treatment options remain limited for patients with melanoma who are wild-type for both BRAF and NRAS (WT/WT). We demonstrate that a subgroup of WT/WT melanomas display high basal phosphorylation of ErbB3 that is associated with autocrine production of the ErbB3 ligand neuregulin-1 (NRG1). In WT/WT melanoma cells displaying high levels of phospho-ErbB3, knockdown of NRG1 reduced cell viability and was associated with decreased phosphorylation of ErbB3, its coreceptor ErbB2, and its downstream target, AKT. Similar effects were observed by targeting ErbB3 with either siRNAs or the neutralizing ErbB3 monoclonal antibodies huHER3-8 and NG33. In addition, pertuzumab-mediated inhibition of ErbB2 heterodimerization decreased AKT phosphorylation, cell growth in vitro, and xenograft growth in vivo. Pertuzumab also potentiated the effects of MEK inhibitor on WT/WT melanoma growth in vitro and in vivo. These findings demonstrate that targeting ErbB3-ErbB2 signaling in a cohort of WT/WT melanomas leads to tumor growth reduction. Together, these studies support the rationale to target the NRG1-ErbB3-ErbB2 axis as a novel treatment strategy in a subset of cutaneous melanomas.