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An ErbB3 Antibody, MM-121, Is Active in Cancers with Ligand-Dependent Activation
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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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“Consistent with these data, blockade of HER3 with the neutralizing antibody MM-121 increases the efficacy of cetuximab in a mouse model of EGFR mutant lung cancer (Schoeberl et al., 2010).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Schoeberl et al., 2010
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Metadata
- 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
- Venue
- Cancer Research
- Published
- 2010-03-14
- Volume
- 70
- Issue
- 6
- Pages
- 2485-2494
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- 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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