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

The NNF Center for Protein Research

42 Citationer (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.

Originalsprog	Engelsk
Artikelnummer	e08153
Tidsskrift	eLife
Vol/bind	4
Sider (fra-til)	1-19
ISSN	2050-084X
DOI	https://doi.org/10.7554/eLife.08153
Status	Udgivet - 1 sep. 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. [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.",

author = "Diego Acosta-Alvear and Cho, {Min Y} and Thomas Wild and Buchholz, {Tonia J} and Lerner, {Alana G} and Olga Simakova and Jamie Hahn and Neha Korde and Ola Landgren and Irina Maric and Choudhary, {Chuna Ram} and Peter Walter and Weissman, {Jonathan S} and Martin Kampmann",

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doi = "10.7554/eLife.08153",

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T1 - Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits

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

Y1 - 2015/9/1

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.

U2 - 10.7554/eLife.08153

DO - 10.7554/eLife.08153

M3 - Journal article

C2 - 26327694

SN - 2050-084X

VL - 4

SP - 1

EP - 19

JO - eLife

JF - eLife

M1 - e08153

ER -

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

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