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Zook P , Pathak HB , Belinsky MG , Gersz L , Devarajan K , Zhou Y , Godwin AK , von Mehren M , Rink L
Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor
Clin Cancer Res. 2017 Jan 01;23(1) :171-180
PMID: 27370604    PMCID: PMC5203981    URL: https://www.ncbi.nlm.nih.gov/pubmed/27370604
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PURPOSE: 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. EXPERIMENTAL DESIGN: 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. (c)2016 AACR.
Zook, Phillip Pathak, Harsh B Belinsky, Martin G Gersz, Lawrence Devarajan, Karthik Zhou, Yan Godwin, Andrew K von Mehren, Margaret Rink, Lori eng P30 CA006927/CA/NCI NIH HHS/ R00 CA158065/CA/NCI NIH HHS/ R01 CA106588/CA/NCI NIH HHS/ 2016/07/03 06:00 Clin Cancer Res. 2017 Jan 1;23(1):171-180. doi: 10.1158/1078-0432.CCR-16-0529. Epub 2016 Jul 1.