Fibroblast-Derived Neuregulin-1 Promotes Compensatory ErbB3 Signaling in Mutant BRAF Melanoma [Cell Biology]

August 12th, 2015 by Capparelli, C., Rosenbaum, S., Berger, A. C., Aplin, A. E.

RAF inhibitors are first-line treatments for patients harboring V600E/K mutant BRAF melanoma. While RAF inhibitors produce high response rates, the degree of tumor regression is heterogeneous. Compensatory/adaptive responses to targeted inhibitors are frequently initiated by the activation of growth factor receptor tyrosine kinases (RTKs) including ErbB3, and factors from the tumor microenvironment may play an important role. We have previously shown that mutant BRAF melanoma cells have enhanced activation of ErbB3 following RAF inhibition; however, the source of neuregulin 1 (NRG1), the ligand for ErbB3, is unknown. In this study, we demonstrate that NRG1 is highly expressed by dermal fibroblasts and cancer associated fibroblasts (CAFs) isolated from mutant BRAF melanomas. Conditioned medium from fibroblasts and CAFs enhanced ErbB3 pathway activation and limited RAF inhibitor cytotoxicity in V600 mutant BRAF-harboring melanomas. Targeting the ErbB3/ErbB2 pathway partially reversed the protective effects of fibroblast/CAF-derived NRG1 on cell growth properties of RAF inhibitor-treated melanoma cells. These findings support the idea that NRG1, acting in a paracrine manner, promotes resistance to RAF inhibitors and emphasize that targeting the ErbB3/ErbB2 pathway will likely improve the efficacy of RAF inhibitors for mutant BRAF melanoma patients.