Disruption of IRE1α through its kinase domain attenuates multiple myeloma.
Aged
Animals
Bortezomib
/ pharmacology
Endoplasmic Reticulum Stress
/ genetics
Endoribonucleases
/ antagonists & inhibitors
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Lenalidomide
/ pharmacology
Male
Mice
Middle Aged
Multiple Myeloma
/ drug therapy
Protein Kinase Inhibitors
/ pharmacology
Protein Serine-Threonine Kinases
/ antagonists & inhibitors
Signal Transduction
/ drug effects
Unfolded Protein Response
/ genetics
X-Box Binding Protein 1
/ genetics
Xenograft Model Antitumor Assays
endoplasmic reticulum stress
inositol-requiring enzyme 1
kinase inhibitors
multiple myeloma
unfolded protein response
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
13 08 2019
13 08 2019
Historique:
pubmed:
3
8
2019
medline:
24
3
2020
entrez:
3
8
2019
Statut:
ppublish
Résumé
Multiple myeloma (MM) arises from malignant immunoglobulin (Ig)-secreting plasma cells and remains an incurable, often lethal disease despite therapeutic advances. The unfolded-protein response sensor IRE1α supports protein secretion by deploying a kinase-endoribonuclease module to activate the transcription factor XBP1s. MM cells may co-opt the IRE1α-XBP1s pathway; however, the validity of IRE1α as a potential MM therapeutic target is controversial. Genetic disruption of IRE1α or XBP1s, or pharmacologic IRE1α kinase inhibition, attenuated subcutaneous or orthometastatic growth of MM tumors in mice and augmented efficacy of two established frontline antimyeloma agents, bortezomib and lenalidomide. Mechanistically, IRE1α perturbation inhibited expression of key components of the endoplasmic reticulum-associated degradation machinery, as well as secretion of Ig light chains and of cytokines and chemokines known to promote MM growth. Selective IRE1α kinase inhibition reduced viability of CD138
Identifiants
pubmed: 31371506
pii: 1906999116
doi: 10.1073/pnas.1906999116
pmc: PMC6697881
doi:
Substances chimiques
Protein Kinase Inhibitors
0
X-Box Binding Protein 1
0
XBP1 protein, human
0
Bortezomib
69G8BD63PP
ERN1 protein, human
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Endoribonucleases
EC 3.1.-
Lenalidomide
F0P408N6V4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
16420-16429Subventions
Organisme : Howard Hughes Medical Institute
Pays : United States
Informations de copyright
Copyright © 2019 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
Conflict of interest statement: J.M.H., A.L.T., A.S., S.A.M., D.A.L., M. Lu, Y.-C.A.C., J.Q., K.T., D.K., E.S., M.M., M.R., H.A.W., W.W., K.C., S.K., M.H.B., S.T.L., W.S., M. Lorenzo, J.W., J.L., T.D.B., A.H., B.H., A.G., R.M.W., D.L., M.-G.B., J.R., and A.A. were employees of Genentech, Inc. during performance of this work.
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