TSC1 loss synergizes with KRAS activation in lung cancer development in the mouse and confers rapamycin sensitivity.
TSC1 loss synergizes with KRAS activation in lung cancer development in the mouse and confers rapamycin sensitivity.
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DOI：
10.1038/onc.2009.452
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发表时间：
2010-03-18
期刊：
影响因子：
8
通讯作者：
Wong, K-K
中科院分区：
文献类型：
--
作者：
Liang, M-C;Ma, J.;Chen, L.;Kozlowski, P.;Qin, W.;Li, D.;Goto, J.;Shimamura, T.;Hayes, D. N.;Meyerson, M.;Kwiatkowski, D. J.;Wong, K-K
生殖系TSC 1或TSC 2突变可导致多发性硬化综合征（TSC），一种累及肺部的错构瘤综合征。为了探索肺癌中TSC 1和KRAS激活之间的潜在相互作用，产生了Tsc 1丢失和KrasG 12 D表达发生在一小部分肺上皮细胞中的小鼠。与单独的KrasG 12 D突变小鼠（中位生存期27.5周）相比，Tsc 1-KrasG 12 D联合突变小鼠的肿瘤潜伏期（中位生存期11.6 - 15.6周）显著降低。Tsc 1-Kras G12 D肿瘤显示出mTORC 1的一致激活，并对雷帕霉素治疗有反应，导致生存率显著提高，而雷帕霉素对单独使用KrasG 12 D的小鼠的癌症影响较小。在86例肺癌标本中，22%的标本存在TSC 1或TSC 2的杂合性缺失。然而，研究的80个肺癌细胞系中没有一个显示出缺乏TSC 1或TSC 2表达的证据，或者对应于完全丧失的信号模式。这些数据表明Tsc 1缺失与Kras突变协同作用，增强小鼠的肺肿瘤发生，但这在人类肺癌中是罕见的事件。雷帕霉素可能对TSC 1/TSC 2功能受限的肺癌患者具有独特的益处。
Germline TSC1 or TSC2 mutations cause Tuberous Sclerosis Complex (TSC), a hamartoma syndrome with lung involvement. To explore the potential interaction between TSC1 and KRAS activation in lung cancer, mice were generated in which Tsc1 loss and KrasG12D expression occur in a small fraction of lung epithelial cells. Mice with combined Tsc1-KrasG12D mutation had dramatically reduced tumor latency (median survival 11.6 – 15.6 weeks) in comparison to KrasG12D alone mutant mice (median survival 27.5 weeks). Tsc1-Kras G12D tumors showed consistent activation of mTORC1, and responded to treatment with rapamycin leading to significantly improved survival, while rapamycin had minor effects on cancers in KrasG12D alone mice. Loss of heterozygosity for TSC1 or TSC2 was found in 22% of 86 human lung cancer specimens. However, none of 80 lung cancer lines studied showed evidence of lack of expression of either TSC1 or TSC2 or a signaling pattern corresponding to complete loss. These data indicate Tsc1 loss synergizes with Kras mutation to enhance lung tumorigenesis in the mouse, but that this is a rare event in human lung cancer. Rapamycin may have unique benefit for lung cancer patients in which TSC1/TSC2 function is limited.
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DOI：
10.1083/jcb.200403069
发表时间：
2004-07-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Harrington LS;Findlay GM;Gray A;Tolkacheva T;Wigfield S;Rebholz H;Barnett J;Leslie NR;Cheng S;Shepherd PR;Gout I;Downes CP;Lamb RF
通讯作者：
Lamb RF
影响因子：
11.5
作者：
Platt, Fiona M.;Hurst, Carolyn D.;Knowles, Margaret A.
通讯作者：
Knowles, Margaret A.
影响因子：
6.2
作者：
Milton, Daniel T.;Riely, Gregory J.;Miller, Vincent A.
通讯作者：
Miller, Vincent A.
影响因子：
64.8
作者：
Ji, Hongbin;Ramsey, Matthew R.;Wong, Kwok-Kin
通讯作者：
Wong, Kwok-Kin
影响因子：
3.6
作者：
Kenerson, H;Dundon, TA;Yeung, RS
通讯作者：
Yeung, RS