title: MERTK receptor tyrosine kinase is a therapeutic target in melanoma.
abstract: Metastatic melanoma is one of the most aggressive forms of cutaneous cancers. Although recent therapeutic advances have prolonged patient survival, the prognosis remains dismal. C-MER proto-oncogene tyrosine kinase (MERTK) is a receptor tyrosine kinase with oncogenic properties that is often overexpressed or activated in various malignancies. Using both protein immunohistochemistry and microarray analyses, we demonstrate that MERTK expression correlates with disease progression. MERTK expression was highest in metastatic melanomas, followed by primary melanomas, while the lowest expression was observed in nevi. Additionally, over half of melanoma cell lines overexpressed MERTK compared with normal human melanocytes; however, overexpression did not correlate with mutations in BRAF or RAS. Stimulation of melanoma cells with the MERTK ligand GAS6 resulted in the activation of several downstream signaling pathways including MAPK/ERK, PI3K/AKT, and JAK/STAT. MERTK inhibition via shRNA reduced MERTK-mediated downstream signaling, reduced colony formation by up to 59%, and diminished tumor volume by 60% in a human melanoma murine xenograft model. Treatment of melanoma cells with UNC1062, a novel MERTK-selective small-molecule tyrosine kinase inhibitor, reduced activation of MERTK-mediated downstream signaling, induced apoptosis in culture, reduced colony formation in soft agar, and inhibited invasion of melanoma cells. This work establishes MERTK as a therapeutic target in melanoma and provides a rationale for the continued development of MERTK-targeted therapies.
authors.affiliation: Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schlegel
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Sambade
authors.forename: Susan
authors.initials: S
authors.lastname: Sather
authors.forename: Stergios J
authors.initials: SJ
authors.lastname: Moschos
authors.forename: Aik-Choon
authors.initials: AC
authors.lastname: Tan
authors.forename: Amanda
authors.initials: A
authors.lastname: Winges
authors.forename: Deborah
authors.initials: D
authors.lastname: DeRyckere
authors.forename: Craig C
authors.initials: CC
authors.lastname: Carson
authors.forename: Dimitri G
authors.initials: DG
authors.lastname: Trembath
authors.forename: John J
authors.initials: JJ
authors.lastname: Tentler
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: Pei-Fen
authors.initials: PF
authors.lastname: Kuan
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hamilton
authors.forename: Lyn M
authors.initials: LM
authors.lastname: Duncan
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Miller
authors.forename: Nana
authors.initials: N
authors.lastname: Nikolaishvili-Feinberg
authors.forename: Bentley R
authors.initials: BR
authors.lastname: Midkiff
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Weihe
authors.initials: W
authors.lastname: Zhang
authors.forename: Chao
authors.initials: C
authors.lastname: Yang
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Frye
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.forename: Janiel M
authors.initials: JM
authors.lastname: Shields
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Graham
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009154:Mutation; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism*; D000076202:c-Mer Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C000715470:MAS1 protein, human; C097072:MERTK protein, human