title: Targeting the HER Family with Pan-HER Effectively Overcomes Resistance to Cetuximab.
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. ©2016 AACR.
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Mari
authors.initials: M
authors.lastname: Iida
authors.affiliation: 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.
authors.forename: Harsh
authors.initials: H
authors.lastname: Bahrar
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Toni M
authors.initials: TM
authors.lastname: Brand
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Hannah E
authors.initials: HE
authors.lastname: Pearson
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: John P
authors.initials: JP
authors.lastname: Coan
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Orbuch
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Bailey G
authors.initials: BG
authors.lastname: Flanigan
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Swick
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Prashanth J
authors.initials: PJ
authors.lastname: Prabakaran
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Johan
authors.initials: J
authors.lastname: Lantto
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Ivan D
authors.initials: ID
authors.lastname: Horak
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Kragh
authors.affiliation: City of Hope, Duarte, California.
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Kimple
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. dlwheeler@wisc.edu.
authors.forename: Deric L
authors.initials: DL
authors.lastname: Wheeler
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung; D002294:Carcinoma, Squamous Cell; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006258:Head and Neck Neoplasms; D006801:Humans; D008297:Male; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors; D000077195:Squamous Cell Carcinoma of Head and Neck; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000068818:Cetuximab; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3