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; von Soly, Szerenke Kiss; 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; Zhou, Han-Jie; Wustrow, David; Rolfe, Mark
Source
Cancer Cell. 28(5)
Subject
Language
Abstract
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.