Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor.
Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor.
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DOI：
10.1038/nm.2091
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发表时间：
2010-02
期刊：
影响因子：
82.9
通讯作者：
Fruman, David A.
中科院分区：
文献类型：
--
作者：
Janes, Matthew R.;Limon, Jose J.;So, Lomon;Chen, Jing;Lim, Raymond J.;Chavez, Melissa A.;Vu, Collin;Lilly, Michael B.;Mallya, Sharmila;Ong, S. Tiong;Konopleva, Marina;Martin, Michael B.;Ren, Pingda;Liu, Yi;Rommel, Christian;Fruman, David A.
靶向雷帕霉素的哺乳动物靶标（mTOR）是癌症治疗的有前途的策略。然而，mTOR激酶在两种复合物TORC 1和TORC 2中起作用，这两种复合物都不被变构抑制剂雷帕霉素或类似物完全抑制。我们比较了雷帕霉素与活性位点TORC 1/2抑制剂PP 242在携带费城染色体（Ph）易位的急性白血病模型中的作用。我们证明，PP 242，而不是雷帕霉素，导致小鼠和人类白血病细胞死亡。在体内，PP 242延迟白血病发作并增强当前一线酪氨酸激酶抑制剂的作用，比雷帕霉素更有效。令人惊讶的是，PP 242对正常淋巴细胞的增殖和功能的作用比雷帕霉素弱得多。PI-103是一种选择性较低的TORC 1/2抑制剂，也靶向磷酸肌醇3-激酶，比PP 242更具免疫抑制作用。这些发现证实Ph+转化细胞比正常淋巴细胞对选择性TORC 1/2抑制剂更敏感，并支持开发此类抑制剂用于白血病治疗。
Targeting the mammalian target of rapamycin (mTOR) is a promising strategy for cancer therapy. However, the mTOR kinase functions in two complexes, TORC1 and TORC2, neither of which is fully inhibited by the allosteric inhibitor rapamycin or analogs. We compared rapamycin with the active-site TORC1/2 inhibitor PP242, in acute leukemia models harboring the Philadelphia chromosome (Ph) translocation. We demonstrate that PP242, but not rapamycin, causes death of mouse and human leukemia cells. In vivo, PP242 delays leukemia onset and augments the effects of current front-line tyrosine kinase inhibitors, more effectively than rapamycin. Surprisingly, PP242 has much weaker effects than rapamycin on proliferation and function of normal lymphocytes. PI-103, a less selective TORC1/2 inhibitor that also targets phosphoinositide 3-kinase, is more immunosuppressive than PP242. These findings establish that Ph+ transformed cells are more sensitive than normal lymphocytes to selective TORC1/2 inhibitors, and support the development of such inhibitors for leukemia therapy.
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影响因子：
4.4
作者：
Durand, Caylib A.;Hartvigsen, Karsten;Gold, Michael R.
通讯作者：
Gold, Michael R.
影响因子：
7.3
作者：
Guertin, David A.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
4
作者：
Huang, Haojie;Tindall, Donald J.
通讯作者：
Tindall, Donald J.
影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1084/jem.189.9.1399
发表时间：
1999-05-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Li S;Ilaria RL Jr;Million RP;Daley GQ;Van Etten RA
通讯作者：
Van Etten RA