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Stromal neuregulin-1 modulates the response to MEK inhibitors in WT BRAF/WT NRAS (WT/WT) melanomas

Capparelli, Claudia, Purwin , Timothy J., Heilman , Shea, Chervoneva, Inna, McCue, Peter, Davies, Michael A., Gershenwald, Jeffrey and Aplin, Andrew E. (2018) Stromal neuregulin-1 modulates the response to MEK inhibitors in WT BRAF/WT NRAS (WT/WT) melanomas. Molecular Cancer Therapeutics, 17 (1). ISSN 15388514


MEK-ERK1/2 signaling is elevated in the majority of melanomas. While MEK inhibitors (MEKi) are FDA-approved for mutant BRAF melanoma, and have some activity against NRAS mutant tumors, they have shown little activity in patients with melanomas that are wild type for BRAF and NRAS (WT/WT). Since the tumor microenvironment (TME) often regulates drug resistance, we tested the effects of growth factors on WT/WT melanoma growth in the presence of MEKi. Neuregulin-1 (NRG1) protected patient-derived WT/WT human melanoma cell lines from growth inhibition mediated by trametinib (MEKi). Phospho-proteomic analysis and clinical grade neutralizing antibodies implicated adaptive activation of ErbB3/ErbB2 complexes in the protective effects of NRG1. NRG1 was detected in fibroblasts and cancer-associated fibroblasts (CAF), and CAFconditioned medium activated ErbB3/ErbB2 signaling in MEK inhibited WT/WT melanoma cells. ErbB3 and ErbB2 neutralizing antibodies blocked the protective effects of fibroblast- and CAF-derived NRG1 in vitro and cooperated with MEKi to delay xenograft growth in vivo. Together our results provide a rationale for the treatment of WT/WT melanomas with the combination of MEKi and anti-ErbB3/ErbB2 antibodies.

Item Type: Article
Date Deposited: 26 Jun 2018 00:45
Last Modified: 25 Jan 2019 00:45


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