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; JOSEPH N. CONTESSA

MOLECULAR CANCER THERAPEUTICS

AMER ASSOC CANCER RESEARCH

Lugar: Philadelphia; Año: 2019

1535-7163

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 thisautocrine 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 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 boththerapeutic modalities identifies NRG as an actionable therapeutic target for improving treatment regimens in HNSCC.