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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Cancer Biology and Translational Studies

Neuregulin Signaling Is a Mechanism of Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma

Marta Baro, Cecilia Lopez Sambrooks, Barbara A. Burtness, Mark A. Lemmon and Joseph N. Contessa
Marta Baro
Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.
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Cecilia Lopez Sambrooks
Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.
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Barbara A. Burtness
Department of Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut.
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Mark A. Lemmon
Department of Pharmacology and Cancer Biology Institute, Yale University, New Haven, Connecticut.
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Joseph N. Contessa
Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.Department of Pharmacology and Cancer Biology Institute, Yale University, New Haven, Connecticut.
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  • For correspondence: joseph.contessa@yale.edu
DOI: 10.1158/1535-7163.MCT-19-0163 Published November 2019
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Abstract

EGFR signaling confers resistance to radiotherapy and is a validated target in head and neck squamous cell carcinoma (HNSCC). The inhibition of EGFR in combination with radiotherapy improves local control and overall survival in these patients; however, therapeutic resistance limits the efficacy of this approach. We therefore sought to identify cellular mechanisms that cause resistance to EGFR inhibition and radiotherapy in HNSCC. Though clonal isolation of carcinoma cells exposed to increasing concentrations of cetuximab, we found that resistant cells upregulate prosurvival ErbB3 and AKT signaling. Using EFM-19 cells and confirmatory analysis of protein levels, we demonstrate that cetuximab resistance is characterized by enhanced neuregulin expression identifying a novel adaptive mechanism of therapeutic resistance. Inhibition of this autocrine loop with CDX-3379 (an ErbB3 specific antibody) was sufficient to block ErbB3/AKT signaling in cetuximab resistant cells. The combination of CDX-3379 and cetuximab reduced proliferation and survival after radiotherapy in several HNSCC cell lines. These in vitro findings were confirmed in xenograft tumor growth experiments including an approach using growth factor–supplemented Matrigel. In vivo, the delivery of EGFR and ErbB3 antibodies significantly reduced tumor growth in cetuximab-resistant FaDu and CAL27 xenografts. In summary, this work demonstrates that autocrine NRG ligand secretion is a mechanism for therapeutic resistance to cetuximab and radiotherapy. This cross-resistance to both therapeutic modalities identifies NRG as an actionable therapeutic target for improving treatment regimens in HNSCC.

Footnotes

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

  • Mol Cancer Ther 2019;18:2124–34

  • Received February 15, 2019.
  • Revision received June 4, 2019.
  • Accepted July 31, 2019.
  • Published first August 6, 2019.
  • ©2019 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 18 (11)
November 2019
Volume 18, Issue 11
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Neuregulin Signaling Is a Mechanism of Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma
Marta Baro, Cecilia Lopez Sambrooks, Barbara A. Burtness, Mark A. Lemmon and Joseph N. Contessa
Mol Cancer Ther November 1 2019 (18) (11) 2124-2134; DOI: 10.1158/1535-7163.MCT-19-0163

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Neuregulin Signaling Is a Mechanism of Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma
Marta Baro, Cecilia Lopez Sambrooks, Barbara A. Burtness, Mark A. Lemmon and Joseph N. Contessa
Mol Cancer Ther November 1 2019 (18) (11) 2124-2134; DOI: 10.1158/1535-7163.MCT-19-0163
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Molecular Cancer Therapeutics
eISSN: 1538-8514
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