Evidence map›Paper›PMID 35853457›Full record

ArticleCell chemical biology2022

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

Ian D Ferguson, Yu-Hsiu T Lin, Christine Lam, Hao Shao, Kevin M Tharp, Martina Hale, Corynn Kasap, Margarette C Mariano, Audrey Kishishita, Bonell Patiño Escobar and 10 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell chemical biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.

0numbers the graph read from it
0cells of the map it votes in
13citing papers in PubMed
2.1field-weighted citation impact, top 12% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

13 citing papers in PubMed, 25 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

20 authors at 4 institutions in 2 countries.

Ian D FergusonDepartment of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA.
Yu-Hsiu T LinDepartment of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA.
Christine LamDepartment of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA.
Hao ShaoInstitute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
Kevin M TharpDepartment of Surgery, University of California, San Francisco, San Francisco CA 94143, USA.
Martina HaleDepartment of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA.
Corynn KasapDepartment of Medicine, Division of Hematology or Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
Margarette C MarianoDepartment of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA.
Audrey KishishitaDepartment of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA; Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, San Francisco, CA 94158, USA.
Bonell Patiño EscobarDepartment of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA.
Kamal MandalDepartment of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA.
Veronica SteriHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Donghui WangHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Paul PhojanakongHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Sami T TuomivaaraDepartment of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA.
Byron HannHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Christoph DriessenDepartment of Oncology and Hematology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
Brian Van NessDepartment of Genetics, Cell Biology & Development, University of Minnesota, Minneapolis, MN 55455, USA.
Jason E GestwickiInstitute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
Arun P WiitaDepartment of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA. Electronic address: arun.wiita@ucsf.edu.
University of California, San Francisco · USUCSF Helen Diller Family Comprehensive Cancer Center · USKantonsspital St. Gallen · CHUniversity of Minnesota · US

Funding

Translational InformaticsP30CA082103 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Alan Ashworth · 1999 to 2026
$209.7M
Molecular Chaperones and Small MoleculesR01NS059690 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Jason E Gestwicki · 2008 to 2026
$7.9M
Project 3 - Modeling Proteasome Inhibitor Response and Resistance in Cell Lines and Patient Samples with Single Cell Analysis of SubpopulationsU54CA224018 · NCI · MAYO CLINIC ARIZONA · PI BERGSAGEL, PETER LEIF · 2017 to 2021
$6.0M
Research Training in Chemistry and Chemical BiologyT32GM145460 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Jason E Gestwicki · 2022 to 2026
$3.1M
Exploiting myeloma proteome remodeling to extend proteasome inhibitor efficacyR01CA226851 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI WIITA, ARUN P. · 2018 to 2022
$1.6M
Global Assessment of Myeloma Response to ChemotherapyK08CA184116 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI WIITA, ARUN P. · 2014 to 2018
$684k
Mechanical stress reprograms mitochondrial metabolism to support tumor survival and invasion through the mitochondrial unfolded protein responseF32CA236156 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI THARP, KEVIN · 2019 to 2021
$110k
NCI NIH HHS F32 CA236156NCI NIH HHS K08 CA184116NCI NIH HHS P30 CA082103NCI NIH HHS R01 CA226851NCI NIH HHS U54 CA224018NIGMS NIH HHS T32 GM145460NINDS NIH HHS R01 NS059690
6 · The paper itself

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.

Indexed as

Antineoplastic AgentsMultiple MyelomaCell Line, TumorHSP70 Heat-Shock ProteinsHumansProteasome Endopeptidase ComplexProteasome InhibitorsProteostasisAntineoplastic AgentsHSP70 Heat-Shock ProteinsProteasome Endopeptidase ComplexProteasome InhibitorsbortezomibHSP70mitochondriamitoribosomemyelomaproteasome inhibitorproteomicsproteostasisresistance

Identifiers

PMID35853457
PMCPMC9434701
OpenAlexW4285810624

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.