title: Antitumor Effects of MEHD7945A, a Dual-Specific Antibody against EGFR and HER3, in Combination with Radiation in Lung and Head and Neck Cancers.
abstract: Human epidermal growth factor receptor family members (EGFR, HER2, HER3, and HER4) play important roles in tumorigenesis and response to cancer therapeutics. In this study, we evaluated the capacity of the dual-target antibody MEHD7945A that simultaneously targets EGFR and HER3 to modulate radiation response in lung and head and neck cancer models. Antitumor effects of MEHD7945A in combination with radiation were evaluated in cell culture and tumor xenograft models. Mechanisms that may contribute to increased radiation killing by MEHD7945A, including DNA damage and inhibition of EGFR-HER signaling pathways, were analyzed. Immunohistochemical analysis of tumor xenografts was conducted to evaluate the effect of MEHD7945A in combination with radiation on tumor growth and microenvironment. MEHD7945A inhibited basal and radiation-induced EGFR and HER3 activation resulting in the inhibition of tumor cell growth and enhanced radiosensitivity. MEHD7945A was more effective in augmenting radiation response than treatment with individual anti-EGFR or anti-HER3 antibodies. An increase in DNA double-strand breaks associated γ-H2AX was observed in cells receiving combined treatment with MEHD7945A and radiation. Immunohistochemical staining evaluation in human tumor xenografts showed that MEHD7945A combined with radiation significantly reduced the expression of markers of tumor proliferation and tumor vasculature. These findings reveal the capacity of MEHD7945A to augment radiation response in lung and head and neck cancers. The dual EGFR/HER3-targeting action of MEHD7945A merits further investigation and clinical trial evaluation as a radiation sensitizer in cancer therapy.
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Chunrong
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Shyhmin
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Armstrong
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: David M
authors.initials: DM
authors.lastname: Francis
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Lauryn R
authors.initials: LR
authors.lastname: Werner
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: Mark X
authors.initials: MX
authors.lastname: Sliwkowski
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Albert
authors.initials: A
authors.lastname: van der Kogel
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. harari@humonc.wisc.edu.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Harari
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000494:pharmacology*; D007150:Immunohistochemistry; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000532:radiotherapy; D011836:Radiation Tolerance / Q000187:drug effects; D018714:Radiotherapy, Adjuvant; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; C569960:MEHD7945A; D066246:ErbB Receptors; D020893:Receptor, ErbB-3