Cited by 264HER2/EGFR in Cancer ResearchLung Cancer Treatments and MutationsPI3K/AKT/mTOR signaling in cancer

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An ErbB3 Antibody, MM-121, Is Active in Cancers with Ligand-Dependent Activation

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Schoeberl, Birgit, Faber, Anthony C., Li, Danan, Liang, Mei-Chih, Crosby, Katherine, Onsum, Matthew, Burenkova, Olga, Pace, Emily, Walton, Zandra, Nie, Lin, Fulgham, Aaron, Song, Youngchul, Nielsen, Ulrik B., Engelman, Jeffrey A., Wong, Kwok-Kin·2010·Cancer Research

DOI 10.1158/0008-5472.can-09-3145PMC PMC2840205

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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.

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Authors: 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.
Affiliations: Harvard University (US)
Corresponding author: Engelman, Jeffrey A.
Wong, Kwok-Kin
ORCID: Schoeberl, Birgit
Faber, Anthony C.
Liang, Mei-Chih
Burenkova, Olga
Pace, Emily
Walton, Zandra
Song, Youngchul
Nielsen, Ulrik B.
Engelman, Jeffrey A.
Wong, Kwok-Kin
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2010-03-14
Volume: 70
Issue: 6
Pages: 2485-2494
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-09-3145
PMC: PMC2840205
OpenAlex: W2120213327
Cited by: 264
References: 31
Citations by year: 2026: 2 · 2024: 5 · 2023: 8 · 2022: 11 · 2021: 10 · 2020: 8 · 2019: 10 · 2018: 19 · 2017: 16 · 2016: 26 · 2015: 31 · 2014: 29 · 2013: 29 · 2012: 29
FWCI: 14.05
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute on Aging (R01AG2400401, K08AG024004, R01AG027757)
National Cancer Institute (P50CA127003, CA120060, R01CA122794, R01CA140594, P50CA090578, K08CA120060, R01CA137008)
Topics: Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords: HER3, ligand-dependent receptor activation, EGFR, HER2, MET, PI3K signaling, gefitinib resistance, cetuximab resistance, neuregulin-1, EGFR inhibitor resistance, xenograft models
MeSH terms: Cetuximab, Gefitinib, Animals, Antibodies, Monoclonal, Cricetulus, Cricetinae, Humans, Ligands, Neoplasms, Quinazolines, CHO Cells, Neuregulin-1, Receptor, ErbB-3, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Antibodies, Monoclonal, Humanized, ErbB Receptors

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An ErbB3 Antibody, MM-121, Is Active in Cancers with Ligand-Dependent Activation

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