Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Edited by Carol Prives, Columbia University, New York, NY, and approved December 5, 2016 (received for review November 22, 2016)
Significance
In previous work, we used genome-wide screening to uncover a counterintuitive mechanism by which cells can acquire resistance to inhibitors of the proteasome’s catalytic core through experimentally induced imbalances in the composition of its regulatory particle. However, in many cases, mechanisms uncovered in vitro for acquired resistance often do not translate to the context of actual clinical cancers. Here, we show that this mechanism is actually deployed spontaneously and naturally in diverse human cancer lines and is associated not only with increased resistance to proteasome inhibitors both in vitro and in the clinic but also is symptomatic of a much more broadly altered state with a unique gene signature and drug targetable vulnerabilities.
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.
Footnotes
- ↵1To whom correspondence should be addressed. Email: petert{at}wi.mit.edu.
↵2Deceased October 27, 2016.
Author contributions: P. Tsvetkov designed research; P.B.G., L.W., and S.L. provided scientific supervision; P. Tsvetkov and Z.B. performed research; M.G. and L.A.G. contributed new reagents/analytic tools; P. Tsvetkov, E.S., D.J., P. Thiru, M.G., and P.B.G. analyzed data; and P. Tsvetkov, S.S., L.W., and S.L. wrote the paper.
Conflict of interest statement: L.A.G. is a consultant for Foundation Medicine, Novartis, Boehringer Ingelheim, and Third Rock; an equity holder in Foundation Medicine; and a member of the Scientific Advisory Board at Warp Drive. L.A.G. receives sponsored research support from Novartis, Astellas, BMS, and Merck.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1619067114/-/DCSupplemental.
Naturally arising proteasome inhibitor resistance
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