A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma

被引：155

作者：

Fan, Qiwen ^{[1
,3
]}

Aksoy, Ozlem ^{[1
,3
]}

Wong, Robyn A. ^{[1
,3
]}

Ilkhanizadeh, Shirin ^{[1
,3
]}

Novotny, Chris J. ^{[2
]}

Gustafson, William C. ^{[3
,4
]}

Truong, Albert Yi-Que ^{[4
,5
]}

Cayanan, Geraldine ^{[1
,3
]}

Simonds, Erin F. ^{[1
,3
]}

Haas-Kogan, Daphne ^{[6
]}

Phillips, Joanna J. ^{[3
,5
]}

Nicolaides, Theodore ^{[4
,5
]}

Okaniwa, Masanori ^{[2
]}

Shokat, Kevan M. ^{[2
]}

Weiss, William A. ^{[1
,3
,4
,5
]}

机构：

[1] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA

[2] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, Howard Hughes Med Inst, San Francisco, CA 94158 USA

[3] Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA

[4] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94158 USA

[5] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94158 USA

[6] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA

来源：

CANCER CELL | 2017年 / 31卷 / 03期

关键词：

GROWTH-FACTOR RECEPTOR; RAPAMYCIN COMPLEX; MAMMALIAN TARGET; MOLECULAR-BASIS; CANCER; ACTIVATION; RESISTANCE; LANDSCAPE; EFFICACY; GLIOMA;

D O I：

10.1016/j.ccell.2017.01.014

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Although signaling from phosphatidylinositol 3-kinase (PI3K) and AKT to mechanistic target of rapamycin (mTOR) is prominently dysregulated in high-grade glial brain tumors, blockade of PI3K or AKT minimally affects downstream mTOR activity in glioma. Allosteric mTOR inhibitors, such as rapamycin, incompletely block mTORC1 compared with mTOR kinase inhibitors (TORKi). Here, we compared RapaLink-1, a TORKi linked to rapamycin, with earlier-generation mTOR inhibitors. Compared with rapamycin and Rapalink-1, TORKi showed poor durability. RapaLink-1 associated with FKBP12, an abundant mTOR-interacting protein, enabling accumulation of RapaLink-1. RapaLink-1 showed better efficacy than rapamycin or TORKi, potently blocking cancer-derived, activating mutants of mTOR. Our study re-establishes mTOR as a central target in glioma and traces the failure of existing drugs to incomplete/nondurable inhibition of mTORC1.

引用

页码：424 / 435

页数：12

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