Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits
- University of California, San Francisco, United States
- University of Copenhagen, Denmark
- Onyx Pharmaceuticals, Inc. an Amgen subsidiary, United States
- National Institutes of Health, United States
- National Cancer Institute, United States
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.
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Human subjects: The registered clinical research trial (NCT01402284) was approved by the National Cancer Institute (NCI) Institutional Review Board (IRB) and complied with the Declaration of Helsinki, the International Conference on Harmonization, and the Guidelines for Good Clinical Practice. All enrolled patients meeting criteria were consented with an IRB-approved document
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This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits
eLife 4:e08153.
https://doi.org/10.7554/eLife.08153
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