IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma.
IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma.
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DOI：
10.1158/1078-0432.ccr-14-1826
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发表时间：
2015-05-01
期刊：
影响因子：
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通讯作者：
Thomas NE
中科院分区：
文献类型：
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作者：
Carson CC;Moschos SJ;Edmiston SN;Darr DB;Nikolaishvili-Feinberg N;Groben PA;Zhou X;Kuan PF;Pandey S;Chan KT;Jordan JL;Hao H;Frank JS;Hopkinson DA;Gibbs DC;Alldredge VD;Parrish E;Hanna SC;Berkowitz P;Rubenstein DS;Miller CR;Bear JE;Ollila DW;Sharpless NE;Conway K;Thomas NE
与痣相比，黑色素瘤中白细胞介素-2诱导的T细胞激酶（ITK）启动子CpG位点甲基化程度较低。然而，ITK在黑色素瘤中的表达尚未确定，需要阐明。ITK特异性单克隆抗体用于探测来自去识别的福尔马林固定的石蜡包埋的肿瘤块或细胞系阵列的切片，并通过免疫组织化学使ITK可视化。ITK蛋白的水平在黑色素瘤细胞系中不同，并且用四种不同的慢病毒构建体转导代表性的细胞系，所述慢病毒构建体各自含有设计用于敲低ITK mRNA水平的shRNA。还测定了选择性ITK抑制剂BI 10 N对细胞系和小鼠模型的影响。ITK蛋白表达随着痣至转移性黑色素瘤的进展而增加。在黑色素瘤细胞系中，ITK的遗传或药理学抑制降低了增殖和迁移，并增加了G 0/G1期细胞的百分比。用BI 10 N处理荷黑色素瘤小鼠可减少ITK表达异种移植物或已建立的自体（Tyr-Cre/Pten null/Braf V600 E）黑色素瘤的生长。我们的结论是ITK，以前被认为是一种免疫细胞特异性蛋白，在黑色素瘤中异常表达，并促进肿瘤的发展和进展。我们发现ITK在大多数转移性黑色素瘤中异常表达，这表明ITK抑制剂可能对黑色素瘤治疗有效。小分子ITK抑制剂在Tyr-Cre/Ptennull/BrafV 600 E小鼠黑素瘤模型中的功效支持这种可能性。
Interleukin-2 inducible T-cell kinase (ITK) promoter CpG sites are hypomethylated in melanomas compared to nevi. The expression of ITK in melanomas, however, has not been established and requires elucidation. An ITK specific monoclonal antibody was used to probe sections from de-identified, formalin-fixed paraffin-embedded tumor blocks or cell line arrays and ITK was visualized by immunohistochemistry. Levels of ITK protein differed among melanoma cell lines and representative lines were transduced with four different lentiviral constructs that each contained an shRNA designed to knockdown ITK mRNA levels. The effects of the selective ITK inhibitor BI 10N on cell lines and mouse models were also determined. ITK protein expression increased with nevus to metastatic melanoma progression. In melanoma cell lines, genetic or pharmacological inhibition of ITK decreased proliferation and migration and increased the percentage of cells in the G0/G1 phase. Treatment of melanoma-bearing mice with BI 10N reduced growth of ITK-expressing xenografts or established autochthonous (Tyr-Cre/Pten null/Braf V600E) melanomas. We conclude that ITK, formerly considered an immune cell-specific protein, is aberrantly expressed in melanoma and promotes tumor development and progression. Our finding that ITK is aberrantly expressed in most metastatic melanomas suggests that inhibitors of ITK may be efficacious for melanoma treatment. The efficacy of a small molecule ITK inhibitor in the Tyr-Cre/Ptennull/BrafV600E mouse melanoma model supports this possibility.