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Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers

Author(s)
Tsvetkov, Peter; Brune, Zarina; Thiru, Prathapan; Ghandi, Mahmoud; Santagata, Sandro; Whitesell, Luke; Sokol, Ethan Samuel; Jin, Dexter X.; Gupta, Piyush; Lindquist, Susan; Garraway, Levi A.; ... Show more Show less
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Abstract
The use of proteasome inhibitors to target cancer’s dependence on altered protein homeostasis has been greatly limited by intrinsic and acquired resistance. Analyzing data from thousands of cancer lines and tumors, we find that those with suppressed expression of one or more 19S proteasome subunits show intrinsic proteasome inhibitor resistance. Moreover, such proteasome subunit suppression is associated with poor outcome in myeloma patients, where proteasome inhibitors are a mainstay of treatment. Beyond conferring resistance to proteasome inhibitors, proteasome subunit suppression also serves as a sentinel of a more global remodeling of the transcriptome. This remodeling produces a distinct gene signature and new vulnerabilities to the proapoptotic drug, ABT-263. This frequent, naturally arising imbalance in 19S regulatory complex composition is achieved through a variety of mechanisms, including DNA methylation, and marks the emergence of a heritably altered and therapeutically relevant state in diverse cancers.
Date issued
2016-12
URI
http://hdl.handle.net/1721.1/111198
Department
Broad Institute of MIT and Harvard; Massachusetts Institute of Technology. Department of Biology; Koch Institute for Integrative Cancer Research at MIT
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Tsvetkov, Peter et al. “Suppression of 19S Proteasome Subunits Marks Emergence of an Altered Cell State in Diverse Cancers.” Proceedings of the National Academy of Sciences 114, 2 (Janaury 2017): 382–387 © 2017 National Academy of Sciences
Version: Final published version
ISSN
0027-8424
1091-6490

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