Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits
Diego Acosta-Alvear,
Min Y Cho,
Thomas Wild,
Tonia J Buchholz,
Alana G Lerner,
Olga Simakova,
Jamie Hahn,
Neha Korde,
Ola Landgren,
Irina Maric,
Chunaram Choudhary,
Peter Walter,
Jonathan S Weissman,
Martin Kampmann
Affiliations
Diego Acosta-Alvear
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, San Francisco, United States
Min Y Cho
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, San Francisco, United States; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
Thomas Wild
The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
Tonia J Buchholz
Onyx Pharmaceuticals, Inc. an Amgen subsidiary, South San Francisco, United States
Alana G Lerner
Onyx Pharmaceuticals, Inc. an Amgen subsidiary, South San Francisco, United States
Olga Simakova
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, United States
Jamie Hahn
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, United States
Neha Korde
Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, United States; Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States
Ola Landgren
Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, United States; Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States
Irina Maric
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, United States
Chunaram Choudhary
The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
Peter Walter
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, San Francisco, United States
Jonathan S Weissman
Howard Hughes Medical Institute, San Francisco, United States; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, San Francisco, United States
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.
