Antitumor Effects of MEHD7945A, a Dual-Specific Antibody against EGFR and HER3, in Combination with Radiation in Lung and Head and Neck Cancers

被引:28
作者
Li, Chunrong [1 ]
Huang, Shyhmin [1 ]
Armstrong, Eric A. [1 ]
Francis, David M. [1 ]
Werner, Lauryn R. [1 ]
Sliwkowski, Mark X. [2 ]
van der Kogel, Albert [1 ]
Harari, Paul M. [1 ]
机构
[1] Univ Wisconsin, Sch Med & Publ Hlth, Dept Human Oncol, Madison, WI 53792 USA
[2] Genentech Inc, San Francisco, CA 94080 USA
关键词
HUMAN TUMOR XENOGRAFTS; TARGETED AGENTS; ACQUIRED-RESISTANCE; IONIZING-RADIATION; GASTRIC-CANCER; THERAPY; CHEMOTHERAPY; TRASTUZUMAB; NORMALIZATION; MECHANISMS;
D O I
10.1158/1535-7163.MCT-15-0155
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 gamma-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. (C) 2015 AACR.
引用
收藏
页码:2049 / 2059
页数:11
相关论文
共 39 条
[1]   ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics [J].
Arteaga, Carlos L. ;
Engelman, Jeffrey A. .
CANCER CELL, 2014, 25 (03) :282-303
[2]   Novel anticancer targets: revisiting ERBB2 and discovering ERBB3 [J].
Baselga, Jose ;
Swain, Sandra M. .
NATURE REVIEWS CANCER, 2009, 9 (07) :463-475
[3]   GENOMIC INSTABILITY IN CANCER Strategies to improve radiotherapy with targeted drugs [J].
Begg, Adrian C. ;
Stewart, Fiona A. ;
Vens, Conchita .
NATURE REVIEWS CANCER, 2011, 11 (04) :239-253
[4]   Exploitable mechanisms for combining drugs with radiation: concepts, achievements and future directions [J].
Bentzen, Soren M. ;
Harari, Paul M. ;
Bernier, Jacques .
NATURE CLINICAL PRACTICE ONCOLOGY, 2007, 4 (03) :172-180
[5]   Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck [J].
Bonner, JA ;
Harari, PM ;
Giralt, J ;
Azarnia, N ;
Shin, DM ;
Cohen, RB ;
Jones, CU ;
Sur, R ;
Raben, D ;
Jassem, J ;
Ove, R ;
Kies, MS ;
Baselga, J ;
Youssoufian, H ;
Amellal, N ;
Rowinsky, EK ;
Ang, KK .
NEW ENGLAND JOURNAL OF MEDICINE, 2006, 354 (06) :567-578
[6]   Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival [J].
Bonner, James A. ;
Harari, Paul M. ;
Giralt, Jordi ;
Cohen, Roger B. ;
Jones, Christopher U. ;
Sur, Ranjan K. ;
Raben, David ;
Baselga, Jose ;
Spencer, Sharon A. ;
Zhu, Junming ;
Youssoufian, Hagop ;
Rowinsky, Eric K. ;
Ang, K. Kian .
LANCET ONCOLOGY, 2010, 11 (01) :21-28
[7]   Multiparameter analysis of vasculature, perfusion and proliferation in human tumour xenografts [J].
Bussink, J ;
Kaanders, JHAM ;
Rijken, PFJW ;
Martindale, CA ;
van der Kogel, AJ .
BRITISH JOURNAL OF CANCER, 1998, 77 (01) :57-64
[8]   HER3 Comes of Age: New Insights into Its Functions and Role in Signaling, Tumor Biology, and Cancer Therapy [J].
Campbell, Marcia R. ;
Amin, Dhara ;
Moasser, Mark M. .
CLINICAL CANCER RESEARCH, 2010, 16 (05) :1373-1383
[9]   EGFR expression is associated with decreased benefit from trastuzumab in the NCCTG N9831 (Alliance) trial [J].
Cheng, H. ;
Ballman, K. ;
Vassilakopoulou, M. ;
Dueck, A. C. ;
Reinholz, M. M. ;
Tenner, K. ;
Gralow, J. ;
Hudis, C. ;
Davidson, N. E. ;
Fountzilas, G. ;
McCullough, A. E. ;
Chen, B. ;
Psyrri, A. ;
Rimm, D. L. ;
Perez, E. A. .
BRITISH JOURNAL OF CANCER, 2014, 111 (06) :1065-1071
[10]   Compensatory ErbB3/c-Src signaling enhances carcinoma cell survival to ionizing radiation [J].
Contessa, JN ;
Abell, A ;
Mikkelsen, RB ;
Valerie, K ;
Schmidt-Ullrich, R .
BREAST CANCER RESEARCH AND TREATMENT, 2006, 95 (01) :17-27