학술논문
Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis.
Document Type
Article
Author
Anderson, Daniel J.; Le Moigne, Ronan; Djakovic, Stevan; Kumar, Brajesh; Rice, Julie; Wong, Steve; Wang, Jinhai; Yao, Bing; Valle, Eduardo; Kiss von Soly, Szerenke; Madriaga, Antonett; Soriano, Ferdie; Menon, Mary-Kamala; Wu, Zhi Yong; Kampmann, Martin; Chen, Yuwen; Weissman, Jonathan S.; Aftab, Blake T.; Yakes, F. Michael; Shawver, Laura
Source
Subject
*HOMEOSTASIS
*CANCER treatment
*ADENOSINE triphosphatase
*UBIQUITINATION
*PATIENT selection
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Language
ISSN
1535-6108
Abstract
Summary 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 irresolvable 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. [ABSTRACT FROM AUTHOR]