Abstract A146: Stromal neuregulin-1 modulates the response to MEK inhibitors in WT BRAF/WT NRAS (WT/WT) melanomas

Abstract

Abstract 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 CAF-conditioned 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. Citation Format: Claudia Capparelli, Timothy J. Purwin, Shea Heilman, Inna Chervoneva, Michael A. Davies, Jeffrey E. Gershenwald, Andrew E. Aplin. Stromal neuregulin-1 modulates the response to MEK inhibitors in WT BRAF/WT NRAS (WT/WT) melanomas [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A146.