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; Chuna Ram Choudhary; Peter Walter; Jonathan S Weissman; Martin Kampmann

doi:10.7554/eLife.08153

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, Chuna Ram Choudhary, Peter Walter, Jonathan S Weissman, Martin Kampmann

Novo Nordisk Foundation Center for Protein Research

42 Citations (Scopus)

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.

Original language	English
Article number	e08153
Journal	eLife
Volume	4
Pages (from-to)	1-19
ISSN	2050-084X
DOIs	https://doi.org/10.7554/eLife.08153
Publication status	Published - 1 Sept 2015

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Acosta-Alvear, D., Cho, M. Y., Wild, T., Buchholz, T. J., Lerner, A. G., Simakova, O., Hahn, J., Korde, N., Landgren, O., Maric, I., Choudhary, C. R., Walter, P., Weissman, J. S., & Kampmann, M. (2015). Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits. eLife, 4, 1-19. Article e08153. https://doi.org/10.7554/eLife.08153

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title = "Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits",

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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AU - Acosta-Alvear, Diego

AU - Cho, Min Y

AU - Wild, Thomas

AU - Buchholz, Tonia J

AU - Lerner, Alana G

AU - Simakova, Olga

AU - Hahn, Jamie

AU - Korde, Neha

AU - Landgren, Ola

AU - Maric, Irina

AU - Choudhary, Chuna Ram

AU - Walter, Peter

AU - Weissman, Jonathan S

AU - Kampmann, Martin

PY - 2015/9/1

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N2 - 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.

AB - 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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JO - eLife

JF - eLife

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ER -

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

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