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Mol Cancer Ther. 2019 Aug 6. pii: molcanther.0163.2019. doi: 10.1158/1535-7163.MCT-19-0163. [Epub ahead of print]

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

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Therapeutic Radiology, Yale University Medical School.
Department of Internal Medicine and Yale Cancer Center, Yale School of Medicine.
Dept. Pharmacology and Cancer Biology Institute, Yale University.
Therapeutic Radiology. Department of Pharmacology, Yale University Medical School


EGFR signaling confers resistance to radiation therapy (RT) and is a validated target in head and neck squamous cell carcinoma (HNSCC). The inhibition of EGFR in combination with RT 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 RT in HNSCC. Though clonal isolation of carcinoma cells exposed to increasing concentrations of cetuximab, we found that resistant cells upregulate pro-survival 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 RT 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 radiation therapy. This cross-resistance to both therapeutic modalities identifies NRG as an actionable therapeutic target for improving treatment regimens in HNSCC.

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