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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Preclinical Development

Inhibition of TGF-β Enhances the In Vivo Antitumor Efficacy of EGF Receptor–Targeted Therapy

Atul Bedi, Xiaofei Chang, Kimberly Noonan, Vui Pham, Rishi Bedi, Elana J. Fertig, Michael Considine, Joseph A. Califano, Ivan Borrello, Christine H. Chung, David Sidransky and Rajani Ravi
Atul Bedi
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Xiaofei Chang
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Kimberly Noonan
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Vui Pham
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Rishi Bedi
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Elana J. Fertig
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Michael Considine
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Joseph A. Califano
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Ivan Borrello
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Christine H. Chung
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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David Sidransky
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Rajani Ravi
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
1Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery; 2Department of Oncology, and 3Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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DOI: 10.1158/1535-7163.MCT-12-0101-T Published November 2012
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Abstract

EGF receptor (EGFR)–targeted monoclonal antibodies (mAb), such as cetuximab, execute their antitumor effect in vivo via blockade of receptor–ligand interactions and engagement of Fcγ receptors on immune effector cells that trigger antibody-dependent cell-mediated cytotoxicity (ADCC). We show that tumors counteract the in vivo antitumor activity of anti-EGFR mAbs by increasing tumor cell-autonomous expression of TGF-β. We show that TGF-β suppresses the expression of key molecular effectors of immune cell–mediated cytotoxicity, including Apo2L/TRAIL, CD95L/FasL, granzyme B, and IFN-γ. In addition to exerting an extrinsic inhibition of the cytotoxic function of immune effectors, TGF-β–mediated activation of AKT provides an intrinsic EGFR-independent survival signal that protects tumor cells from immune cell–mediated apoptosis. Treatment of mice-bearing xenografts of human head and neck squamous cell carcinoma with cetuximab resulted in emergence of resistant tumor cells that expressed relatively higher levels of TGF-β compared with untreated tumor-bearing mice. Although treatment with cetuximab alone forced the natural selection of TGF-β–overexpressing tumor cells in nonregressing tumors, combinatorial treatment with cetuximab and a TGF-β–blocking antibody prevented the emergence of such resistant tumor cells and induced complete tumor regression. Therefore, elevated levels of TGF-β in the tumor microenvironment enable tumor cells to evade ADCC and resist the antitumor activity of cetuximab in vivo. Our results show that TGF-β is a key molecular determinant of the de novo and acquired resistance of cancers to EGFR-targeted mAbs, and provide a rationale for combinatorial targeting of TGF-β to improve anti-EGFR–specific antibody therapy of EGFR-expressing cancers. Mol Cancer Ther; 11(11); 2429–39. ©2012 AACR.

This article is featured in Highlights of This Issue, p. 2309

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received February 2, 2012.
  • Revision received July 3, 2012.
  • Accepted August 9, 2012.
  • ©2012 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 11 (11)
November 2012
Volume 11, Issue 11
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Inhibition of TGF-β Enhances the In Vivo Antitumor Efficacy of EGF Receptor–Targeted Therapy
Atul Bedi, Xiaofei Chang, Kimberly Noonan, Vui Pham, Rishi Bedi, Elana J. Fertig, Michael Considine, Joseph A. Califano, Ivan Borrello, Christine H. Chung, David Sidransky and Rajani Ravi
Mol Cancer Ther November 1 2012 (11) (11) 2429-2439; DOI: 10.1158/1535-7163.MCT-12-0101-T

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Inhibition of TGF-β Enhances the In Vivo Antitumor Efficacy of EGF Receptor–Targeted Therapy
Atul Bedi, Xiaofei Chang, Kimberly Noonan, Vui Pham, Rishi Bedi, Elana J. Fertig, Michael Considine, Joseph A. Califano, Ivan Borrello, Christine H. Chung, David Sidransky and Rajani Ravi
Mol Cancer Ther November 1 2012 (11) (11) 2429-2439; DOI: 10.1158/1535-7163.MCT-12-0101-T
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