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Allosteric HSP70 inhibitors in Proteasome Inhibitor Resistant Multiple Myeloma

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 cytosolic heat shock protein 70 (HSP70) chaperones as potential targets, consistent with proposed mechanisms of myeloma tumor cells overcoming PI-induced stress. These results led us to explore allosteric HSP70 inhibitors (JG compounds) as myeloma therapeutics. We showed these compounds exhibit increased efficacy against acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Surprisingly, shotgun and pulsed-SILAC mass spectrometry found that JGs have the most pronounced effect on the proteome not through inhibiting cytosolic HSP70s but instead through mitochondrial-localized HSP70, HSPA9/mortalin, 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 myeloma proteostasis networks under therapeutic pressure while motivating further investigation of HSPA9 as a specific vulnerability in PI-resistant disease.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Cell Suspension Culture, Cell Culture

DISEASE(S): Multiple Myeloma

SUBMITTER: Ian Ferguson

LAB HEAD: Arun Wiita

PROVIDER: PXD032030 | Pride | 2022-05-27

REPOSITORIES: Pride

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Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma, dataset 2

Project description:Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating this resistance, we mapped genetic co-dependencies associated with the proteasome. These studies identified cytosolic heat shock protein 70 (HSP70) chaperones as a potential target, mirroring recent studies that have shown mechanism of overcoming PI-induced stress. Here, we first underscore this relationship by mapping genetic co-dependencies in cancer proteostasis. These results lead us to explore HSP70 inhibitors as potential 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 response to PI. 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. This dataset corresponds to experiment outlined in figure 4a.

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Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma

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Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma

Project description: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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Project description:Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma

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Cytosolic splice isoform of Hsp70 nucleotide exchange factor Fes1 is required for the degradation of misfolded proteins in yeast

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Expression data from B220+ Hspa9+/+ and Hspa9+/- CFU-PreB colonies isolated on Day 7 of culture

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Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

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