title: An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation.
abstract: ErbB3 is a critical activator of phosphoinositide 3-kinase (PI3K) signaling in epidermal growth factor receptor (EGFR; ErbB1), ErbB2 [human epidermal growth factor receptor 2 (HER2)], and [hepatocyte growth factor receptor (MET)] addicted cancers, and reactivation of ErbB3 is a prominent method for cancers to become resistant to ErbB inhibitors. In this study, we evaluated the in vivo efficacy of a therapeutic anti-ErbB3 antibody, MM-121. We found that MM-121 effectively blocked ligand-dependent activation of ErbB3 induced by either EGFR, HER2, or MET. Assessment of several cancer cell lines revealed that MM-121 reduced basal ErbB3 phosphorylation most effectively in cancers possessing ligand-dependent activation of ErbB3. In those cancers, MM-121 treatment led to decreased ErbB3 phosphorylation and, in some instances, decreased ErbB3 expression. The efficacy of single-agent MM-121 was also examined in xenograft models. A machine learning algorithm found that MM-121 was most effective against xenografts with evidence of ligand-dependent activation of ErbB3. We subsequently investigated whether MM-121 treatment could abrogate resistance to anti-EGFR therapies by preventing reactivation of ErbB3. We observed that an EGFR mutant lung cancer cell line (HCC827), made resistant to gefitinib by exogenous heregulin, was resensitized by MM-121. In addition, we found that a de novo lung cancer mouse model induced by EGFR T790M-L858R rapidly became resistant to cetuximab. Resistance was associated with an increase in heregulin expression and ErbB3 activation. However, concomitant cetuximab treatment with MM-121 blocked reactivation of ErbB3 and resulted in a sustained and durable response. Thus, these results suggest that targeting ErbB3 with MM-121 can be an effective therapeutic strategy for cancers with ligand-dependent activation of ErbB3.
authors.affiliation: Merrimack Pharmaceuticals, Inc, Cambridge, Massachusetts, USA.
authors.forename: Birgit
authors.initials: B
authors.lastname: Schoeberl
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Faber
authors.forename: Danan
authors.initials: D
authors.lastname: Li
authors.forename: Mei-Chih
authors.initials: MC
authors.lastname: Liang
authors.forename: Katherine
authors.initials: K
authors.lastname: Crosby
authors.forename: Matthew
authors.initials: M
authors.lastname: Onsum
authors.forename: Olga
authors.initials: O
authors.lastname: Burenkova
authors.forename: Emily
authors.initials: E
authors.lastname: Pace
authors.forename: Zandra
authors.initials: Z
authors.lastname: Walton
authors.forename: Lin
authors.initials: L
authors.lastname: Nie
authors.forename: Aaron
authors.initials: A
authors.lastname: Fulgham
authors.forename: Youngchul
authors.initials: Y
authors.lastname: Song
authors.forename: Ulrik B
authors.initials: UB
authors.lastname: Nielsen
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D016466:CHO Cells; D045744:Cell Line, Tumor; D000068818:Cetuximab; D006224:Cricetinae; D003412:Cricetulus; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000077156:Gefitinib; D006801:Humans; D008024:Ligands; D051379:Mice; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D020890:Neuregulin-1 / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D008024:Ligands; D020890:Neuregulin-1; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D000068818:Cetuximab; D000077156:Gefitinib