Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits

  1. Diego Acosta-Alvear
  2. Min Y Cho
  3. Thomas Wild
  4. Tonia J Buchholz
  5. Alana G Lerner
  6. Olga Simakova
  7. Jamie Hahn
  8. Neha Korde
  9. Ola Landgren
  10. Irina Maric
  11. Chunaram Choudhary
  12. Peter Walter
  13. Jonathan S Weissman  Is a corresponding author
  14. Martin Kampmann
  1. University of California, San Francisco, United States
  2. University of Copenhagen, Denmark
  3. Onyx Pharmaceuticals, Inc. an Amgen subsidiary, United States
  4. National Institutes of Health, United States
  5. 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.

Article and author information

Author details

  1. Diego Acosta-Alvear

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  2. Min Y Cho

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  3. Thomas Wild

    The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
  4. Tonia J Buchholz

    Onyx Pharmaceuticals, Inc. an Amgen subsidiary, South San Francisco, United States
    Competing interests
    Tonia J Buchholz, is an employee of Onyx Pharmaceuticals, an Amgen subsidiary.
  5. Alana G Lerner

    Onyx Pharmaceuticals, Inc. an Amgen subsidiary, South San Francisco, United States
    Competing interests
    Alana G Lerner, is an employee of Onyx Pharmaceuticals, an Amgen subsidiary.
  6. Olga Simakova

    Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  7. Jamie Hahn

    Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  8. Neha Korde

    Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, United States
    Competing interests
    No competing interests declared.
  9. Ola Landgren

    Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, United States
    Competing interests
    No competing interests declared.
  10. Irina Maric

    Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  11. Chunaram Choudhary

    The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
  12. Peter Walter

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  13. Jonathan S Weissman

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    For correspondence
    Jonathan.Weissman@ucsf.edu
    Competing interests
    No competing interests declared.
  14. Martin Kampmann

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

Ethics

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

Copyright

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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https://doi.org/10.7554/eLife.08153

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