title: ErbB3-ErbB2 Complexes as a Therapeutic Target in a Subset of Wild-type BRAF/NRAS Cutaneous Melanomas.
abstract: 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.
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Claudia
authors.initials: C
authors.lastname: Capparelli
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Sheera
authors.initials: S
authors.lastname: Rosenbaum
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Berman-Booty
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York.
authors.forename: Amel
authors.initials: A
authors.lastname: Salhi
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Nadège
authors.initials: N
authors.lastname: Gaborit
authors.affiliation: Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhan
authors.affiliation: Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Inna
authors.initials: I
authors.lastname: Chervoneva
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jason
authors.initials: J
authors.lastname: Roszik
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Woodman
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Yulius Y
authors.initials: YY
authors.lastname: Setiady
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York.
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Yarden
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. aea004@jefferson.edu.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Aplin
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D058990:Molecular Targeted Therapy; D020890:Neuregulin-1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms; D000096142:Cutaneous Malignant Melanoma
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D020890:Neuregulin-1; D048493:Proto-Oncogene Proteins B-raf; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C094131:NRG1 protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; C482119:BRAF protein, human; C579846:NRAS protein, human; C485206:pertuzumab