title: Function-blocking ERBB3 antibody inhibits the adaptive response to RAF inhibitor.
abstract: ERBB3/HER3 expression and signaling are upregulated in mutant BRAF melanoma as an adaptive, prosurvival response to FDA-approved RAF inhibitors. Because compensatory ERBB3 signaling counteracts the effects of RAF inhibitors, cotargeting ERBB3 may increase the efficacy of RAF inhibitors in mutant BRAF models of melanoma. Here, we corroborate this concept by showing that the ERBB3 function-blocking monoclonal antibody huHER3-8 can inhibit neuregulin-1 activation of ERBB3 and downstream signaling in RAF-inhibited melanoma cells. Targeting mutant BRAF in combination with huHER3-8 decreased cell proliferation and increased cell death in vitro, and decreased tumor burden in vivo, compared with targeting either mutant BRAF or ERBB3 alone. Furthermore, the likelihood of a durable tumor response in vivo was increased when huHER3-8 was combined with RAF inhibitor PLX4720. Together, these results offer a preclinical proof of concept for the application of ERBB3-neutralizing antibodies to enhance the efficacy of RAF inhibitors in melanoma to delay or prevent tumor regrowth. As ERBB3 is often upregulated in response to other kinase-targeted therapeutics, these findings may have implications for other cancers as well.
authors.affiliation: Department of Cancer Biology and Kimmel Cancer Center; Jefferson College of Graduate Studies;
authors.forename: Curtis H
authors.initials: CH
authors.lastname: Kugel
authors.affiliation: Department of Cancer Biology and Kimmel Cancer Center;
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hartsough
authors.affiliation: Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; and.
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: Department of Cancer Biology and Kimmel Cancer Center; Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Andrew.Aplin@Jefferson.edu.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Aplin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D064593:Heterografts; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D015398:Signal Transduction; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D000077484:Vemurafenib
chemical_list: D000911:Antibodies, Monoclonal; D007211:Indoles; C528407:PLX 4720; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf