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

TitleParadoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits.
Publication TypeJournal Article
Year of Publication2015
AuthorsAcosta-Alvear D, Cho MY, Wild T, Buchholz TJ, Lerner AG, Simakova O, Hahn J, Korde N, Landgren O, Maric I, Choudhary C, Walter P, Weissman JS, Kampmann M
JournalElife
Volume4
Paginatione08153
Date Published2015
ISSN2050-084X
KeywordsAntineoplastic Agents, Cell Line, Tumor, Drug Resistance, Neoplasm, Humans, Multiple Myeloma, Oligopeptides, Proteasome Endopeptidase Complex, Proteasome Inhibitors
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.

DOI10.7554/eLife.08153
Alternate JournalElife
PubMed ID26327694
PubMed Central IDPMC4602331
Grant ListK99 CA181494 / CA / NCI NIH HHS / United States
R00 CA181494 / CA / NCI NIH HHS / United States
R00 CA181494 / CA / NCI NIH HHS / United States
U01 CA168370 / CA / NCI NIH HHS / United States
U01 CA168370 / CA / NCI NIH HHS / United States