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

ELife
Diego Acosta-AlvearMartin Kampmann

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.

Associated Clinical Trials

Jul 26, 2011·Dickran Kazandjian, M.D., Dickran Kazandjian, M.D.

References

Mar 18, 1999·Nature Genetics·G GiaeverR W Davis
Jul 21, 2006·Leukemia·B G M DurieUNKNOWN International Myeloma Working Group
Dec 22, 2006·The Journal of Biological Chemistry·Sovan SarkarDavid C Rubinsztein
Feb 20, 2007·Cancer Research·Silke MeisterReinhard E Voll
Jun 21, 2007·The Journal of Biological Chemistry·Serhiy PankivTerje Johansen
Feb 16, 2008·Science·William E BalchJeffery W Kelly
Jul 16, 2008·Nature Methods·David K BreslowJonathan S Weissman
Nov 7, 2008·The Journal of Biological Chemistry·Erwann RousseauAnne Bertolotti
Jan 10, 2009·Nature Protocols·Da Wei HuangRichard A Lempicki
Sep 11, 2009·Leukemia·J J Shah, R Z Orlowski
Dec 22, 2009·Nature·Martin SchwickartVishva M Dixit
Oct 5, 2010·Oncotarget·Yulia N Demchenko, W Michael Kuehl
Sep 6, 2011·Molecular & Cellular Proteomics : MCP·Sebastian A WagnerChunaram Choudhary
Sep 29, 2011·Biochimica Et Biophysica Acta·Dieter H Wolf, Alexandra Stolz
Oct 7, 2011·Journal of Oncology·Marc J BraunsteinOlcay Batuman
Aug 30, 2012·Nature Methods·Caroline A SchneiderKevin W Eliceiri
Sep 11, 2012·Molecular Cell·Amila SuraweeraAnne Bertolotti
Nov 28, 2012·Current Pharmaceutical Design·Daniela BuacQ Ping Dou
Jan 8, 2013·Trends in Biochemical Sciences·Chang-Wei Liu, Andrew D Jacobson
Jun 7, 2013·Proceedings of the National Academy of Sciences of the United States of America·Martin KampmannJonathan S Weissman
Aug 2, 2013·The New England Journal of Medicine·María-Victoria MateosJesús-F San Miguel
Sep 3, 2013·Biochimica Et Biophysica Acta·Marion Schmidt, Daniel Finley
Dec 30, 2014·Lancet·Christoph RölligMartin Bornhäuser

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Citations

Dec 29, 2016·Proceedings of the National Academy of Sciences of the United States of America·Peter TsvetkovSusan Lindquist
Sep 2, 2017·Proteomics·Marta MendesJ Ignacio Casal
Oct 19, 2017·Cancer Metastasis Reviews·Yulin ChenXing Guo
Aug 2, 2018·Nature Reviews. Molecular Cell Biology·Adrien Rousseau, Anne Bertolotti
Mar 8, 2019·ELife·Blake W TyeL Stirling Churchman
May 28, 2019·Nature Chemical Biology·Peter TsvetkovTodd R Golub
Feb 9, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·David J Sherman, Jing Li
Sep 14, 2020·Asia-Pacific Journal of Clinical Oncology·Yang Bai, Xing Su
Sep 9, 2016·American Journal of Physiology. Cell Physiology·Thibault MayorMichael H Glickman
May 11, 2017·Chemical Communications : Chem Comm·Martin Kampmann
May 6, 2017·Nature Communications·David W MorgensMichael C Bassik
Jul 12, 2018·Cell Death & Disease·Peter TsvetkovYosef Shaul
Aug 28, 2020·Frontiers in Bioengineering and Biotechnology·Ksenia M ShakirovaErdem B Dashinimaev
Apr 30, 2016·The Journal of Biological Chemistry·Vanessa WelkSilke Meiners
Jul 25, 2017·BMC Bioinformatics·Tamas Nagy, Martin Kampmann
Jan 23, 2020·Nature Communications·Avital Eisenberg-LernerYifat Merbl
Nov 3, 2020·The FEBS Journal·Harvey E Johnston, Rahul S Samant
Nov 27, 2020·Nature Communications·Kaushik BhattacharyaDidier Picard
Aug 28, 2020·Cell Reports·Thomas MeulSilke Meiners
Nov 14, 2020·Nature Communications·Sonia BrockwayMarc L Mendillo
Apr 10, 2021·Essays in Biochemistry·Chi Wai YipJay W Shin
Apr 23, 2021·Proceedings of the National Academy of Sciences of the United States of America·Paula Saavedra-GarcíaHolger W Auner
Jun 3, 2021·Cancers·Mélody CaillotBrigitte Sola
Sep 22, 2021·Nature Communications·John DeSistoAdam L Green

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Methods Mentioned

BETA
deubiquitination
Enzyme-linked immunoabsorbent assay
flow cytometry
transfection
PCR

Clinical Trials Mentioned

NCT01323751

Software Mentioned

GraphPad
DataPrism
MaxQuant
gimap
Prism
Excel
Database for Annotation , Visualization and Integrated Discove...
Andromeda
DIVA
CFX Manager

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