Abstract
Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating resistance, we first mapped proteasome-associated genetic co-dependencies. We identified heat shock protein 70 (HSP70) chaperones as potential targets, consistent with proposed mechanisms of myeloma cells overcoming PI-induced stress. We therefore explored allosteric HSP70 inhibitors (JG compounds) as myeloma therapeutics. JG compounds exhibited increased efficacy against acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Shotgun and pulsed SILAC mass spectrometry demonstrated that JGs unexpectedly impact myeloma proteostasis by destabilizing the 55S mitoribosome. Our data suggest JGs have the most pronounced anti-myeloma effect not through inhibiting cytosolic HSP70 proteins but instead through mitochondrial-localized HSP70, HSPA9/mortalin. Analysis of myeloma patient data further supports strong effects of global proteostasis capacity, and particularly HSPA9 expression, on PI response. Our results characterize myeloma proteostasis networks under therapeutic pressure while motivating further investigation of HSPA9 as a specific vulnerability in PI-resistant disease.
Original language | English (US) |
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Pages (from-to) | 1288-1302.e7 |
Journal | Cell Chemical Biology |
Volume | 29 |
Issue number | 8 |
DOIs | |
State | Published - Aug 18 2022 |
Bibliographical note
Funding Information:We thank Drs. Tom Martin, Nina Shah, Sandy Wong, and Jeffrey Wolf for insightful discussions; Multiple Myeloma Research Foundation for sponsoring the CoMMpass study; Dr. Martin Kampmann for providing sgRNA sequences for HSPA9 knockdown and CRISPRi cell line; Dr. Juan A. Oses-Prieto and the University of California, San Francisco (UCSF) Mass Spectrometry Facility; and Drs. DeLaine Larsen and Kari Herrington and the UCSF Nikon Imaging Core for insightful discussions and technical assistance. This study was supported by Gabrielle's Angel Foundation for Cancer Research; UCSF Stephen and Nancy Grand Multiple Myeloma Translational Initiative; NIH grants DP2 OD022552, K08 CA184116, and R01 CA226851 (to A.P.W.), F32CA236156 (to K.M.T.), R01 NS059690 and DoD PC180716 (to J.E.G.), and P30 CA082103 (to B.H.). Graphical abstract was made in BioRender.com. I.D.F. C.L. H.S. J.E.G. and A.P.W. conceived and designed the study. I.D.F. C.L. H.S. K.M.T. M.H. C.K. M.C.M. A.K. V.S. D.W. P.P. S.T.T. and B.H. performed experiments and analyzed data. Y.-H.T.L. performed bioinformatics analyses. C.D. and B.V.N. provided cell line reagents. B.H. J.E.G. and A.P.W. obtained funding. I.D.F. and A.P.W. wrote the manuscript with input from all authors. J.E.G. and H.S. have filed a patent related to the structures of the JG compounds. A.P.W. is an equity holder and scientific advisory board member of Indapta Therapeutics and Protocol Intelligence. The other authors declare no competing interests.
Funding Information:
We thank Drs. Tom Martin, Nina Shah, Sandy Wong, and Jeffrey Wolf for insightful discussions; Multiple Myeloma Research Foundation for sponsoring the CoMMpass study; Dr. Martin Kampmann for providing sgRNA sequences for HSPA9 knockdown and CRISPRi cell line; Dr. Juan A. Oses-Prieto and the University of California, San Francisco (UCSF) Mass Spectrometry Facility; and Drs. DeLaine Larsen and Kari Herrington and the UCSF Nikon Imaging Core for insightful discussions and technical assistance. This study was supported by Gabrielle's Angel Foundation for Cancer Research; UCSF Stephen and Nancy Grand Multiple Myeloma Translational Initiative; NIH grants DP2 OD022552 , K08 CA184116 , and R01 CA226851 (to A.P.W.), F32CA236156 (to K.M.T.), R01 NS059690 and DoD PC180716 (to J.E.G.), and P30 CA082103 (to B.H.). Graphical abstract was made in BioRender.com .
Publisher Copyright:
© 2022 Elsevier Ltd
Keywords
- HSP70
- bortezomib
- mitochondria
- mitoribosome
- myeloma
- proteasome inhibitor
- proteomics
- proteostasis
- resistance