title: Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor.
abstract: OBJECTIVE
  Gastrointestinal stromal tumors (GIST) generally harbor activating mutations in the receptor tyrosine kinase KIT or in the related platelet-derived growth factor receptor alpha (PDGFRA). GIST treated with imatinib mesylate or second-line therapies that target mutant forms of these receptors generally escape disease control and progress over time. Inhibiting additional molecular targets may provide more substantial disease control. Recent studies have implicated the PI3K/AKT pathway in the survival of imatinib mesylate-resistant GIST cell lines and tumors.
  
  
  METHODS
  Here, we performed in vitro and in vivo studies evaluating the novel combination of imatinib mesylate with the AKT inhibitor MK-2206 in GIST. Whole-transcriptome sequencing (WTS) of xenografts was performed to explore the molecular aspects of tumor response to this novel combination and to potentially identify additional therapeutic targets in GIST.
  
  
  RESULTS
  This drug combination demonstrated significant synergistic effects in a panel of imatinib mesylate-sensitive and -resistant GIST cell lines. Furthermore, combination therapy provided significantly greater efficacy, as measured by tumor response and animal survival, in imatinib mesylate-sensitive GIST xenografts as compared with treatment with imatinib mesylate or MK-2206 alone. WTS implicated two neural genes, brain expressed X-linked 1 and neuronal pentraxin I, whose expression was significantly upregulated in combination-treated tumors compared with tumors treated with the two monotherapies.
  
  
  CONCLUSIONS
  These studies provide strong preclinical justification for combining imatinib mesylate with an AKT inhibitor as a front-line therapy in GIST. In addition, the WTS implicated the BCL-2/BAX/BAD apoptotic pathway as a potential mechanism for this enhanced combination effect. Clin Cancer Res; 23(1); 171-80. ©2016 AACR.
authors.affiliation: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Zook
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Harsh B
authors.initials: HB
authors.lastname: Pathak
authors.affiliation: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Belinsky
authors.affiliation: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Gersz
authors.affiliation: Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Karthik
authors.initials: K
authors.lastname: Devarajan
authors.affiliation: Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.affiliation: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: von Mehren
authors.affiliation: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Rink
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020869:Gene Expression Profiling; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D000073359:Exome Sequencing; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit