Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits Journal Article
| Authors: | Acosta-Alvear, D.; Cho, M. Y.; Wild, T.; Buchholz, T. J.; Lerner, A. G.; Simakova, O.; Hahn, J.; Korde, N.; Landgren, O.; Maric, I.; Choudhary, C.; Walter, P.; Weissman, J. S.; Kampmann, M. |
| Article Title: | Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits |
| Abstract: | Hallmarks of cancer, including rapid growth and aneuploidy, can result in non-oncogene addiction to the proteostasis network that can be exploited clinically. The defining example is the exquisite sensitivity of multiple myeloma (MM) to 20S proteasome inhibitors, such as carfilzomib. However, MM patients invariably acquire resistance to these drugs. Using a next-generation shRNA platform, we found that proteostasis factors, including chaperones and stress-response regulators, controlled the response to carfilzomib. Paradoxically, 19S proteasome regulator knockdown induced resistance to carfilzomib in MM and non-MM cells. 19S subunit knockdown did not affect the activity of the 20S subunits targeted by carfilzomib nor their inhibition by the drug, suggesting an alternative mechanism, such as the selective accumulation of protective factors. In MM patients, lower 19S levels predicted a diminished response to carfilzomib-based therapies. Together, our findings suggest that an understanding of network rewiring can inform development of new combination therapies to overcome drug resistance. © 2015 eLife Sciences Publications Ltd. All rights reserved. |
| Keywords: | protein expression; lenalidomide; clinical trial; nonhuman; validation process; mass spectrometry; cell viability; reverse transcription polymerase chain reaction; bortezomib; multiple myeloma; gene expression; cell growth; protein degradation; viral gene delivery system; immune response; protein synthesis; gene identification; lentivirus vector; retrovirus vector; immunoblotting; gene control; protein subunit; protein folding; bioinformatics; short hairpin rna; carfilzomib; protein homeostasis; desensitization; next generation sequencing; article; 19s proteasomal subunit |
| Journal Title: | eLife |
| Volume: | 4 |
| ISSN: | 2050-084X |
| Publisher: | eLife Sciences Publications Ltd. |
| Date Published: | 2015-09-01 |
| Start Page: | e08153 |
| Language: | English |
| DOI: | 10.7554/eLife.08153 |
| PROVIDER: | scopus |
| PMCID: | PMC4602331 |
| PUBMED: | 26327694 |
| DOI/URL: | |
| Notes: | Export Date: 2 December 2015 -- Source: Scopus |
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