title: Paracrine Effect of NRG1 and HGF Drives Resistance to MEK Inhibitors in Metastatic Uveal Melanoma.
abstract: Uveal melanoma patients with metastatic disease usually die within one year, emphasizing an urgent need to develop new treatment strategies for this cancer. MEK inhibitors improve survival in cutaneous melanoma patients but show only modest efficacy in metastatic uveal melanoma patients. In this study, we screened for growth factors that elicited resistance in newly characterized metastatic uveal melanoma cell lines to clinical-grade MEK inhibitors, trametinib and selumetinib. We show that neuregulin 1 (NRG1) and hepatocyte growth factor (HGF) provide resistance to MEK inhibition. Mechanistically, trametinib enhances the responsiveness to NRG1 and sustained HGF-mediated activation of AKT. Individually targeting ERBB3 and cMET, the receptors for NRG1 and HGF, respectively, overcome resistance to trametinib provided by these growth factors and by conditioned medium from fibroblasts that produce NRG1 and HGF. Inhibition of AKT also effectively reverses the protective effect of NRG1 and HGF in trametinib-treated cells. Uveal melanoma xenografts growing in the liver in vivo and a subset of liver metastases of uveal melanoma patients express activated forms of ERBB2 (the coreceptor for ERBB3) and cMET. Together, these results provide preclinical evidence for the use of MEK inhibitors in combination with clinical-grade anti-ERBB3 or anti-cMET monoclonal antibodies in metastatic uveal melanoma.
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Hanyin
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Mizue
authors.initials: M
authors.lastname: Terai
authors.affiliation: Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Ken
authors.initials: K
authors.lastname: Kageyama
authors.affiliation: Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Shinji
authors.initials: S
authors.lastname: Ozaki
authors.affiliation: Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Peter A
authors.initials: PA
authors.lastname: McCue
authors.affiliation: Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Takami
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Andrew.Aplin@Jefferson.edu.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Aplin
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020890:Neuregulin-1 / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014604:Uveal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; C066855:HGF protein, human; C094131:NRG1 protein, human; D020890:Neuregulin-1; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D017228:Hepatocyte Growth Factor; C581292:ERBB3 protein, human; D019859:Proto-Oncogene Proteins c-met; D020893:Receptor, ErbB-3; D020930:MAP Kinase Kinase Kinases