Effect of PI3K- and mTOR-specific inhibitors on spontaneous B-cell follicular lymphomas in PTEN/LKB1-deficient mice.
Effect of PI3K- and mTOR-specific inhibitors on spontaneous B-cell follicular lymphomas in PTEN/LKB1-deficient mice.
复制标题
DOI：
10.1038/bjc.2011.83
复制
发表时间：
2011-03-29
影响因子：
8.8
通讯作者：
Duce, S. L.
中科院分区：
文献类型：
--
作者：
Garcia-Martinez, J. M.;Wullschleger, S.;Preston, G.;Guichard, S.;Fleming, S.;Alessi, D. R.;Duce, S. L.
PI 3 K-mTOR（磷酸肌醇3-激酶-雷帕霉素激酶的哺乳动物靶点）途径在大多数肿瘤中被激活，并且有兴趣评估PI 3 K或mTOR激酶的抑制剂是否具有治疗癌症的功效。在这里，我们定义了目前在临床试验中的特异性mTOR（AZD 8055）和PI 3 K（GDC-0941）抑制剂在治疗PTEN+/− LKB 1 +/hypo小鼠中发生的自发性B细胞滤泡性淋巴瘤中的有效性。给予PTEN+/− LKB 1 +/hypo小鼠AZD 8055或GDC-0941，并通过MRI测量B细胞滤泡性淋巴瘤的体积。通过免疫组织化学、免疫印迹和流式细胞术分析肿瘤样品。AZD 8055或GDC-0941在2周内诱导肿瘤体积减少约40%，并伴有AKT、S6 K和SGK（血清和糖皮质激素蛋白激酶）蛋白激酶磷酸化的消融。这些药物减少了肿瘤细胞增殖，促进了细胞凋亡，抑制了中心母细胞群。AZD 8055或GDC-0941治疗超过3周导致肿瘤体积适度额外减少，治疗6周后达到初始体积的50%。停止药物治疗后，肿瘤以增加的速率重新生长，并显示出与对照未治疗肿瘤相似的高级别和弥漫性形态。这些结果定义了新设计的特异性mTOR和PI 3 K抑制剂对自发性肿瘤模型的影响，这可能比经常用于评估激酶抑制剂有效性的异种移植模型更具代表性。我们的数据表明，mTOR和PI 3 K抑制剂将有利于治疗PI 3 K通路被不适当激活的癌症;然而，单独给药时，可能不会导致此类肿瘤的完全消退。
The PI3K–mTOR (phosphoinositide 3-kinase–mammalian target of rapamycin kinase) pathway is activated in the majority of tumours, and there is interest in assessing whether inhibitors of PI3K or mTOR kinase have efficacy in treating cancer. Here, we define the effectiveness of specific mTOR (AZD8055) and PI3K (GDC-0941) inhibitors, currently in clinical trials, in treating spontaneous B-cell follicular lymphoma that develops in PTEN+/−LKB1+/hypo mice. The PTEN+/−LKB1+/hypo mice were administered AZD8055 or GDC-0941, and the volumes of B-cell follicular lymphoma were measured by MRI. Tumour samples were analysed by immunohistochemistry, immunoblot and flow cytometry. The AZD8055 or GDC-0941 induced ∼40% reduction in tumour volume within 2 weeks, accompanied by ablation of phosphorylation of AKT, S6K and SGK (serum and glucocorticoid protein kinase) protein kinases. The drugs reduced tumour cell proliferation, promoted apoptosis and suppressed centroblast population. The AZD8055 or GDC-0941 treatment beyond 3 weeks caused a moderate additional decrease in tumour volume, reaching ∼50% of the initial volume after 6 weeks of treatment. Tumours grew back at an increased rate and displayed similar high grade and diffuse morphology as the control untreated tumours upon cessation of drug treatment. These results define the effects that newly designed and specific mTOR and PI3K inhibitors have on a spontaneous tumour model, which may be more representative than xenograft models frequently employed to assess effectiveness of kinase inhibitors. Our data suggest that mTOR and PI3K inhibitors would benefit treatment of cancers in which the PI3K pathway is inappropriately activated; however, when administered alone, may not cause complete regression of such tumours.
登录
查看更多内容
有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
4.1
作者：
Murray, JT;Campbell, DG;Cohen, P
通讯作者：
Cohen, P
影响因子：
3.9
作者：
Salphati, Laurent;Wong, Harvey;Wallin, Jeffrey J.
通讯作者：
Wallin, Jeffrey J.
DOI：
10.1073/pnas.96.4.1563
发表时间：
1999-02-16
影响因子：
11.1
作者：
Podsypanina, K;Ellenson, LH;Parsons, R
通讯作者：
Parsons, R
影响因子：
10.5
作者：
Chen, Mei-Ling;Xu, Pei-Zhang;Hay, Nissim
通讯作者：
Hay, Nissim