Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma. Issue 8 (18th August 2022)

• Record Type: Journal Article
• Authors: Ferguson, Ian D.; Lin, Yu-Hsiu T.; Lam, Christine; Shao, Hao; Tharp, Kevin M.; Hale, Martina; Kasap, Corynn; Mariano, Margarette C.; Kishishita, Audrey; Patiño Escobar, Bonell; Mandal, Kamal; Steri, Veronica; Wang, Donghui; Phojanakong, Paul; Tuomivaara, Sami T.; Hann, Byron; Driessen, Christoph; Van Ness, Brian; Gestwicki, Jason E.; Wiita, Arun P.
• Is Part Of: Cell chemical biology. Volume 29:Issue 8(2022)
• Page Start: 1288
• Page End: 1302.e7
• Publication Date: 2022-08-18
• Subjects: HSP70 -- myeloma -- proteasome inhibitor -- proteomics -- proteostasis -- mitoribosome -- mitochondria -- resistance -- bortezomib; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2022.06.010
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical abstract: Highlights: JGs have increased potency against proteasome inhibitor-resistant multiple myeloma JG compounds accumulate in mitochondria and lead to depletion of mitoribosome subunits Patient data reveal HSPA9 expression as determinant of response to proteasome inhibitors Abstract : Ferguson et al. find that a class of HSP70 inhibitors (JG compounds) have increased potency against myeloma cells resistant to proteasome inhibitors. JGs localize to mitochondria, inhibit the mitochondrial HSP70, and deplete mitochondrial ribosome proteins. Patient data analysis further links mitochondrial protein homeostasis to proteasome inhibitor resistance in myeloma.