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Ref Type Journal Article
PMID (27370604)
Authors Zook P, Pathak HB, Belinsky MG, Gersz L, Devarajan K, Zhou Y, Godwin AK, von Mehren M, Rink L
Title Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 23
Issue 1
Date 2017 Jan 01
URL
Abstract Text 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.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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT exon11 KIT A829P gastrointestinal stromal tumor sensitive Imatinib + MK2206 Preclinical - Cell culture Actionable In a preclinical study, the combination of Gleevec (imatinib) and MK2206 demonstrated synergy in inhibiting growth of a Gleevec (imatinib)-resistant gastrointestinal stromal tumor cell line harboring a KIT exon 11 mutation and KIT A829P in culture (PMID: 27370604). 27370604
KIT exon13 gastrointestinal stromal tumor sensitive Imatinib + MK2206 Preclinical - Cell culture Actionable In a preclinical study, the combination of Gleevec (imatinib) and MK2206 demonstrated synergy in inhibiting growth of a gastrointestinal stromal tumor cell line harboring a KIT exon 13 mutation in culture (PMID: 27370604). 27370604
KIT exon11 gastrointestinal stromal tumor sensitive Imatinib + MK2206 Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Gleevec (imatinib) and MK2206 increased growth inhibition and decreased viability of gastrointestinal stromal tumor (GIST) cell lines harboring KIT exon 11 mutations in culture, and improved survival and inhibited tumor growth in a KIT exon 11-mutant GIST cell line xenograft model, with increased efficacy compared to either agent alone (PMID: 27370604). 27370604
KIT exon11 KIT V654A gastrointestinal stromal tumor sensitive Imatinib + MK2206 Preclinical - Cell culture Actionable In a preclinical study, the combination of Gleevec (imatinib) and MK2206 demonstrated synergy in inhibiting growth of a Gleevec (imatinib)-resistant gastrointestinal stromal tumor cell line harboring a KIT exon 11 deletion mutation and KIT V654A in culture (PMID: 27370604). 27370604