Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits.
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.
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.|Howard Hughes Medical Institute, San Francisco, United States.
Diego
D
Acosta-Alvear
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.
Min Y
MY
Cho
The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
Thomas
T
Wild
Onyx Pharmaceuticals, Inc. an Amgen subsidiary, South San Francisco, United States.
Tonia J
TJ
Buchholz
Onyx Pharmaceuticals, Inc. an Amgen subsidiary, South San Francisco, United States.
Alana G
AG
Lerner
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, United States.
Olga
O
Simakova
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, United States.
Jamie
J
Hahn
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.
Neha
N
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
O
Landgren
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, United States.
Irina
I
Maric
The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
Chunaram
C
Choudhary
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.|Howard Hughes Medical Institute, San Francisco, United States.
Peter
P
Walter
Howard Hughes Medical Institute, San Francisco, United States.|Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.
Jonathan S
JS
Weissman
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.|Howard Hughes Medical Institute, San Francisco, United States.
Martin
http://orcid.org/0000-0002-3819-7019
M
Kampmann
D000970:Antineoplastic Agents / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009101:Multiple Myeloma / Q000201:enzymology*; D009842:Oligopeptides / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000378:metabolism*
D000970:Antineoplastic Agents; D009842:Oligopeptides; D061988:Proteasome Inhibitors; C524865:carfilzomib; D046988:Proteasome Endopeptidase Complex
cancer; carfilzomib; cell biology; human; myeloma; proteasome; proteostasis