title: Dasatinib suppression of medulloblastoma survival and migration is markedly enhanced by combining treatment with the aurora kinase inhibitor AT9283.
abstract: Medulloblastoma (MB) expresses Src kinase, while aurora kinase A overexpression correlates with poor survival. We thus investigated novel combination treatment with dasatinib and AT9283, inhibitors of Src and aurora kinase, respectively, on MB growth in vitro and in vivo. Treatment with each drug significantly reduced cell viability and combined treatment markedly potentiated this response. AT9283 induced p53 expression, autophagy, and G2/M cell-cycle arrest, while combined treatment induced S phase arrest. Dasatinib treatment caused tumor regression in vivo. Activated Src was detected in 44% MB analyzed. We conclude that further evaluation of this combination therapy for MB is highly warranted.
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, 1760 Haygood Drive, HSRB E-384, Atlanta, GA 30322, USA.
authors.forename: William
authors.initials: W
authors.lastname: Petersen
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, 1760 Haygood Drive, HSRB E-384, Atlanta, GA 30322, USA.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, 1760 Haygood Drive, HSRB E-384, Atlanta, GA 30322, USA.
authors.forename: Liangping
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, 1760 Haygood Drive, HSRB E-384, Atlanta, GA 30322, USA.
authors.forename: Hongying
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Schneiderjan
authors.affiliation: Departments of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, 1760 Haygood Drive, HSRB E-384, Atlanta, GA 30322, USA. Electronic address: tobey.macdonald@emory.edu.
authors.forename: Tobey J
authors.initials: TJ
authors.lastname: MacDonald
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D001343:Autophagy; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D000069439:Dasatinib; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016195:G2 Phase; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C535237:1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C495901:TP53 protein, human; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D014508:Urea; D064096:Aurora Kinase A; D000069439:Dasatinib
keywords: Aurora kinase; Dasatinib; Medulloblastoma; Survival
references.citation: Nat Rev Mol Cell Biol. 2003 Nov;4(11):842-54
references.pmid: 14625535
references.citation: Pediatr Blood Cancer. 2010 Jul 15;55(1):35-41
references.pmid: 20232424
references.citation: Nat Biotechnol. 2009 Jan;27(1):77-83
references.pmid: 19098899
references.citation: Blood. 2007 Sep 15;110(6):2034-40
references.pmid: 17495131
references.citation: Acta Neuropathol. 2012 Apr;123(4):465-72
references.pmid: 22134537
references.citation: Anticancer Drugs. 2010 Apr;21(4):339-50
references.pmid: 20016367
references.citation: Biochim Biophys Acta. 1996 Jun 7;1287(2-3):121-49
references.pmid: 8672527
references.citation: Cancer Cell. 2011 Mar 8;19(3):372-86
references.pmid: 21397860
references.citation: Oncogene. 2012 Mar 8;31(10):1217-27
references.pmid: 21785464
references.citation: Blood. 2008 Aug 15;112(4):1005-12
references.pmid: 18477770
references.citation: Ann Oncol. 2011 Feb;22(2):431-7
references.pmid: 20924078
references.citation: Cancer Res. 2004 May 1;64(9):3103-11
references.pmid: 15126347
references.citation: Cancer Res. 2009 Jul 15;69(14):5987-95
references.pmid: 19567681
references.citation: Curr Treat Options Neurol. 2012 Aug;14(4):416-26
references.pmid: 22622599
references.citation: J Clin Oncol. 2011 Mar 1;29(7):839-44
references.pmid: 21263099
references.citation: J Neurooncol. 2011 Jan;101(2):215-26
references.pmid: 20524040
references.citation: J Pharmacol Exp Ther. 2012 Dec;343(3):617-27
references.pmid: 22935731
references.citation: J Clin Oncol. 2011 Apr 10;29(11):1408-14
references.pmid: 20823417
references.citation: Mol Cancer Ther. 2013 Apr;12(4):460-70
references.pmid: 23358665
references.citation: J Med Chem. 2009 Jan 22;52(2):379-88
references.pmid: 19143567
references.citation: Blood. 2010 Sep 23;116(12):2089-95
references.pmid: 20548094
references.citation: Nat Genet. 2001 Oct;29(2):143-52
references.pmid: 11544480
references.citation: J Clin Oncol. 2011 Apr 10;29(11):1400-7
references.pmid: 20921458
references.citation: Biostatistics. 2003 Apr;4(2):249-64
references.pmid: 12925520
references.citation: Ann Oncol. 2012 May;23(5):1307-1313
references.pmid: 22015452
references.citation: J Clin Oncol. 1999 Mar;17(3):832-45
references.pmid: 10071274
references.citation: Cancer Res. 2008 Mar 15;68(6):1768-76
references.pmid: 18339857
references.citation: FASEB J. 2010 Aug;24(8):2881-92
references.pmid: 20354138
references.citation: Eur J Cancer. 2012 Oct;48(15):2417-30
references.pmid: 22244830
references.citation: Mol Cancer Ther. 2009 May;8(5):1137-47
references.pmid: 19417143
references.citation: Invest New Drugs. 2013 Feb;31(1):39-45
references.pmid: 22669335
references.citation: Pediatr Blood Cancer. 2013 Aug;60(8):1350-7
references.pmid: 23444345
references.citation: Pediatr Blood Cancer. 2010 Jul 15;55(1):26-34
references.pmid: 20108338
references.citation: Clin Cancer Res. 2007 Jun 15;13(12):3682-8
references.pmid: 17575233
references.citation: N Engl J Med. 2013 Feb 14;368(7):651-62
references.pmid: 23406030
references.citation: Mol Cancer. 2013 Mar 05;12:18
references.pmid: 23497290
references.citation: Expert Opin Investig Drugs. 2010 Mar;19(3):415-25
references.pmid: 20113198
references.citation: Clin Cancer Res. 2012 Nov 1;18(21):6058-64
references.pmid: 22988055
references.citation: J Clin Oncol. 2011 Apr 10;29(11):1424-30
references.pmid: 21098324
references.citation: Expert Opin Investig Drugs. 2010 Aug;19(8):931-45
references.pmid: 20557276
references.citation: Cancer Metastasis Rev. 2003 Dec;22(4):451-64
references.pmid: 12884918