Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis

被引：329

作者：

Anderson, Daniel J. ^{[1
]}

Le Moigne, Ronan ^{[1
]}

Djakovic, Stevan ^{[1
]}

Kumar, Brajesh ^{[1
]}

Rice, Julie ^{[1
]}

Wong, Steve ^{[1
]}

Wang, Jinhai ^{[1
]}

Yao, Bing ^{[1
]}

Valle, Eduardo ^{[1
]}

von Soly, Szerenke Kiss ^{[1
]}

Madriaga, Antonett ^{[1
]}

Soriano, Ferdie ^{[1
]}

Menon, Mary-Kamala ^{[1
]}

Wu, Zhi Yong ^{[1
]}

Kampmann, Martin ^{[2
,3
]}

Chen, Yuwen ^{[2
,3
]}

Weissman, Jonathan S. ^{[2
,3
]}

Aftab, Blake T. ^{[4
]}

Yakes, F. Michael ^{[1
]}

Shawver, Laura ^{[1
]}

Zhou, Han-Jie ^{[1
]}

Wustrow, David ^{[1
]}

Rolfe, Mark ^{[1
]}

机构：

[1] Cleave Biosci Inc, Burlingame, CA 94010 USA

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

[3] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA

[4] Univ Calif San Francisco, Helen Diller Family Canc Ctr, Dept Med, Div Hematol & Oncol, San Francisco, CA 94158 USA

来源：

CANCER CELL | 2015年 / 28卷 / 05期

基金：

美国国家卫生研究院;

关键词：

UBIQUITIN-PROTEASOME SYSTEM; INHIBITOR PS-341; CELL LINE; ER STRESS; VCP/P97; AUTOPHAGY; DEGRADATION; RESISTANCE; BORTEZOMIB; APOPTOSIS;

D O I：

10.1016/j.ccell.2015.10.002

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

p97 is a AAA-ATPase with multiple cellular functions, one of which is critical regulation of protein homeostasis pathways. We describe the characterization of CB-5083, a potent, selective, and orally bioavailable inhibitor of p97. Treatment of tumor cells with CB-5083 leads to accumulation of poly-ubiquitinated proteins, retention of endoplasmic reticulum-associated degradation (ERAD) substrates, and generation of irre-solvable proteotoxic stress, leading to activation of the apoptotic arm of the unfolded protein response. In xenograft models, CB-5083 causes modulation of key p97-related pathways, induces apoptosis, and has antitumor activity in a broad range of both hematological and solid tumor models. Molecular determinants of CB-5083 activity include expression of genes in the ERAD pathway, providing a potential strategy for patient selection.

引用

页码：653 / 665

页数：13

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