Abstract
Abstract Metastatic uveal melanoma (UM) patients usually die within one year, emphasizing an urgent need to develop new treatment strategies. Mitogen-activated protein kinase kinase (MEK) small molecule inhibitors improve survival in cutaneous melanoma patients but show only modest efficacy in UM patients. In this study, we identified compensatory mechanisms that provide resistance to MEK inhibition in metastatic UM. We screened for growth factors that were able to induce resistance in three newly characterized metastatic UM cell lines to MEK inhibitors, trametinib and selumetinib, with colony formation assay and viability assay. Cellular signaling pathway analysis was carried out to determine the molecular mechanisms of resistance to MEK inhibition in metastatic UM cells. Clinical-grade antibody and inhibitors targeting these pathways were used to determine their capability to overcome the resistance mediated by these growth factors. Conditioned medium collected from fibroblasts were used to evaluate whether stromal effect from fibroblasts could drive resistance to metastatic UM cells. We demonstrate that Neuregulin 1 (NRG1) and hepatocyte growth factor (HGF) provide resistance to MEK inhibition. Mechanistically, trametinib enhances the responsiveness to NRG1, whereas HGF induces sustained activation of AKT in the presence of trametinib. Individually targeting ERBB3 and cMET, the receptors for NRG1 and HGF, overcomes resistance to trametinib provided by these growth factors and by conditioned medium from fibroblasts, which produce NRG1 and HGF. Analysis of metastatic liver biopsies showed that ERBB2, which is the co-receptor for NRG1, and cMET were phosphorylated in some of these clinical specimens. Our data suggest that combination of MEK inhibitors with ERBB3 and cMET targeting agents may provide novel and effective treatment strategies in metastatic UM. Citation Format: Hanyin Cheng, Mizue Terai, Takami Sato, Andrew Aplin. Paracrine effect of NRG1 and HGF drives resistance to MEK inhibitors in metastatic uveal melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2685. doi:10.1158/1538-7445.AM2015-2685
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