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Mol Cancer Ther. 2016 Sep;15(9):2175-86. doi: 10.1158/1535-7163.MCT-16-0012. Epub 2016 Jul 15.

Targeting the HER Family with Pan-HER Effectively Overcomes Resistance to Cetuximab.

Author information

1
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
2
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. Radboud Department of Radiation Oncology, University Medical Centre Nijmegen, Nijmegen, the Netherlands.
3
Symphogen A/S, Ballerup, Denmark.
4
City of Hope, Duarte, California.
5
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. dlwheeler@wisc.edu.

Abstract

Cetuximab, an antibody against the EGFR, has shown efficacy in treating head and neck squamous cell carcinoma (HNSCC), metastatic colorectal cancer, and non-small cell lung cancer (NSCLC). Despite the clinical success of cetuximab, many patients do not respond to cetuximab. Furthermore, virtually all patients who do initially respond become refractory, highlighting both intrinsic and acquired resistance to cetuximab as significant clinical problems. To understand mechanistically how cancerous cells acquire resistance, we previously developed models of acquired resistance using the H226 NSCLC and UM-SCC1 HNSCC cell lines. Cetuximab-resistant clones showed a robust upregulation and dependency on the HER family receptors EGFR, HER2, and HER3. Here, we examined pan-HER, a mixture of six antibodies targeting these receptors on cetuximab-resistant clones. In cells exhibiting acquired or intrinsic resistance to cetuximab, pan-HER treatment decreased all three receptors' protein levels and downstream activation of AKT and MAPK. This correlated with decreased cell proliferation in cetuximab-resistant clones. To determine whether pan-HER had a therapeutic benefit in vivo, we established de novo cetuximab-resistant mouse xenografts and treated resistant tumors with pan-HER. This regimen resulted in a superior growth delay of cetuximab-resistant xenografts compared with mice continued on cetuximab. Furthermore, intrinsically cetuximab-resistant HNSCC patient-derived xenograft tumors treated with pan-HER exhibited significant growth delay compared with vehicle/cetuximab controls. These results suggest that targeting multiple HER family receptors simultaneously with pan-HER is a promising treatment strategy for tumors displaying intrinsic or acquired resistance to cetuximab. Mol Cancer Ther; 15(9); 2175-86.

PMID:
27422810
PMCID:
PMC5010956
[Available on 2017-03-01]
DOI:
10.1158/1535-7163.MCT-16-0012
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

of Potential Conflicts of Interest: D.L. Wheeler holds a laboratory research agreement with Symphogen A/S. J. Lantto, I.D. Horak, and M. Kragh are employed by Symphogen A/S. No potential conflicts of interest were disclosed by other authors.

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