title: Co-targeting HGF/cMET Signaling with MEK Inhibitors in Metastatic Uveal Melanoma.
abstract: Patients with metastatic uveal melanoma usually die within 1 year of diagnosis, emphasizing an urgent need to develop new treatment strategies. The liver is the most common site of metastasis. Mitogen-activated protein kinase kinase (MEK) inhibitors improve survival in V600 BRAF-mutated cutaneous melanoma patients but have limited efficacy in patients with uveal melanoma. Our previous work showed that hepatocyte growth factor (HGF) signaling elicits resistance to MEK inhibitors in metastatic uveal melanoma. In this study, we demonstrate that expression of two BH3-only family proteins, Bim-EL and Bmf, contributes to HGF-mediated resistance to MEK inhibitors. Targeting HGF/cMET signaling with LY2875358, a neutralizing and internalizing anti-cMET bivalent antibody, and LY2801653, a dual cMET/RON inhibitor, overcomes resistance to trametinib provided by exogenous HGF and by conditioned medium from primary hepatic stellate cells. We further determined that activation of PI3Kα/γ/δ isoforms mediates the resistance to MEK inhibitors by HGF. Combination of LY2801653 with trametinib decreases AKT phosphorylation and promotes proapoptotic PARP cleavage in metastatic uveal melanoma explants. Together, our data support the notion that selectively blocking cMET signaling or PI3K isoforms in metastatic uveal melanoma may break the intrinsic resistance to MEK inhibitors provided by factors from stromal cells in the liver.Mol Cancer Ther; 16(3); 516-28. ©2017 AACR.
authors.affiliation: Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Hanyin
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Vivian
authors.initials: V
authors.lastname: Chua
authors.affiliation: Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Connie
authors.initials: C
authors.lastname: Liao
authors.affiliation: Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Purwin
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 Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
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 and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Andrew.Aplin@Jefferson.edu.|Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Aplin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics; D055166:Hepatic Stellate Cells / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D014604:Uveal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000098943:Uveal Melanoma
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D017228:Hepatocyte Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met; D011728:Pyridones; D011744:Pyrimidinones; C486655:BMF protein, human; C554061:GNAQ protein, human; C560077:trametinib