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| Status |
Public on Apr 15, 2020 |
| Title |
Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating resistance, we first map proteasome-associated genetic co-dependencies. We identify cytosolic heat shock protein 70 (HSP70) chaperones as a potential target, consistent with proposed mechanisms of myeloma tumor cells overcoming PI-induced stress. These results led us to explore allosteric HSP70 inhibitors as myeloma therapeutics. We show these compounds exhibit increased efficacy against both acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Surprisingly, shotgun and pulsed-SILAC proteomics reveal that JG’s overcome PI resistance not via the expected mechanism of inhibiting cytosolic HSP70s, but instead through mitochondrial-localized HSP70, HSPA9, destabilizing the 55S mitoribosome. Analysis of myeloma patient data further supports strong effects of global proteostasis capacity, and particularly HSPA9 expression, on PI response. Our results characterize dynamics of myeloma proteostasis networks under therapeutic pressure while further motivating investigation of HSPA9 as a specific target in PI-resistant disease.
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| Overall design |
Data uploaded here: RNA-sequencing of MM.1S myeloma cells were treated with allosteric HSP70 inhibitor JG342 at 350nM or DMSO control for 26 hours in biological duplicate.
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| Contributor(s) |
Ferguson ID, Wiita A |
| Citation missing |
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| Submission date |
Apr 14, 2020 |
| Last update date |
Apr 15, 2020 |
| Contact name |
Ian Daniel Ferguson |
| E-mail(s) |
ifergus@stanford.edu
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| Organization name |
Stanford University
|
| Department |
Cancer Biology PhD program
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| Street address |
265 Campus Dr
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| City |
Stanford |
| State/province |
CA |
| ZIP/Postal code |
94305 |
| Country |
USA |
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| Platforms (1) |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA625299 |
| SRA |
SRP256353 |
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