title: UNC2025, a MERTK Small-Molecule Inhibitor, Is Therapeutically Effective Alone and in Combination with Methotrexate in Leukemia Models.
abstract: Purpose:MERTK tyrosine kinase is ectopically expressed in 30% to 50% of acute lymphoblastic leukemias (ALL) and more than 80% of acute myeloid leukemias (AML) and is a potential therapeutic target. Here, we evaluated the utility of UNC2025, a MERTK tyrosine kinase inhibitor, for treatment of acute leukemia.Experimental Design:Preclinicalin vitroandin vivoassays using cell lines and primary leukemia patient samples were used to evaluate antileukemic effects of UNC2025.Results:UNC2025 potently inhibited prosurvival signaling, induced apoptosis, and reduced proliferation and colony formation in MERTK-expressing ALL and AML cell lines and patient samples. Approximately 30% of primary leukemia patient samples (78 of 261 total) were sensitive to UNC2025. Sensitive samples were most prevalent in the AML, T-ALL, and minimally differentiated (M0) AML subsets. UNC2025 inhibited MERTK in bone marrow leukemia cells and had significant therapeutic effects in xenograft models, with dose-dependent decreases in tumor burden and consistent two-fold increases in median survival, irrespective of starting disease burden. In a patient-derived AML xenograft model, treatment with UNC2025 induced disease regression. In addition, UNC2025 increased sensitivity to methotrexatein vivo, suggesting that addition of MERTK-targeted therapy to current cytotoxic regimens may be particularly effective and/or allow for chemotherapy dose reduction.Conclusions:The broad-spectrum activity mediated by UNC2025 in leukemia patient samples and xenograft models, alone or in combination with cytotoxic chemotherapy, supports continued development of MERTK inhibitors for treatment of leukemia.Clin Cancer Res; 23(6); 1481-92. ©2016 AACR.
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia.|Department of Pediatrics, Emory University, Atlanta, Georgia.
authors.forename: Deborah
authors.initials: D
authors.lastname: DeRyckere
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Alisa B
authors.initials: AB
authors.lastname: Lee-Sherick
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia.|Department of Pediatrics, Emory University, Atlanta, Georgia.
authors.forename: Madeline G
authors.initials: MG
authors.lastname: Huey
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Hill
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Knight Cancer Institute, Portland, Oregon.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia.|Department of Pediatrics, Emory University, Atlanta, Georgia.|Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Jacobsen
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Lauren S
authors.initials: LS
authors.lastname: Page
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Kirkpatrick
authors.affiliation: Institute of Environmental Health and Division of Environmental and Biomolecular Systems, Oregon Health and Science University, Portland, Oregon.
authors.forename: Fatma
authors.initials: F
authors.lastname: Eryildiz
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.|Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Montgomery
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Weihe
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina.|Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Frye
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.|Departments of Medicine and Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia. Douglas.Graham@choa.org.|Department of Pediatrics, Emory University, Atlanta, Georgia.
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Graham
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008727:Methotrexate / Q000008:administration & dosage*; D051379:Mice; D010879:Piperazines / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays; D000076202:c-Mer Tyrosine Kinase / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D010879:Piperazines; C000597431:UNC2025; C097072:MERTK protein, human; D000076202:c-Mer Tyrosine Kinase; D000225:Adenine; D008727:Methotrexate