An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation.
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.
Schoeberl
Birgit
B
Merrimack Pharmaceuticals, Inc, Cambridge, Massachusetts, USA.
Faber
Anthony C
AC
Li
Danan
D
Liang
Mei-Chih
MC
Crosby
Katherine
K
Onsum
Matthew
M
Burenkova
Olga
O
Pace
Emily
E
Walton
Zandra
Z
Nie
Lin
L
Fulgham
Aaron
A
Song
Youngchul
Y
Nielsen
Ulrik B
UB
Engelman
Jeffrey A
JA
Wong
Kwok-Kin
KK
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
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