An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation

Birgit Schoeberl, Anthony C. Faber, Danan Li, Mei-Chih Liang, Katherine Crosby, Matthew Onsum, Olga Burenkova, Emily Pace, Zandra Walton, Lin Nie, Aaron Fulgham, Youngchul Song, Ulrik B. Nielsen, Jeffrey A. Engelman, Kwok Kin Wong

Research output: Contribution to journalArticle

208 Scopus citations

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.

Original languageEnglish
Pages (from-to)2485-2494
Number of pages10
JournalCancer Research
Volume70
Issue number6
DOIs
StatePublished - 15 Mar 2010

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    Schoeberl, B., Faber, A. C., Li, D., Liang, M-C., Crosby, K., Onsum, M., Burenkova, O., Pace, E., Walton, Z., Nie, L., Fulgham, A., Song, Y., Nielsen, U. B., Engelman, J. A., & Wong, K. K. (2010). An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. Cancer Research, 70(6), 2485-2494. https://doi.org/10.1158/0008-5472.CAN-09-3145