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Proc Natl Acad Sci U S A. 2019 Aug 13;116(33):16420-16429. doi: 10.1073/pnas.1906999116. Epub 2019 Aug 1.

Disruption of IRE1α through its kinase domain attenuates multiple myeloma.

Author information

1
Cancer Immunology, Genentech, Inc., South San Francisco, CA 94080.
2
Translational Oncology, Genentech, Inc., South San Francisco, CA 94080.
3
Pathology, Genentech, Inc., South San Francisco, CA 94080.
4
Structural Biology, Genentech, Inc., South San Francisco, CA 94080.
5
Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, CA 94080.
6
Microchemistry, Proteomics and Lipidomics, Genentech, Inc., South San Francisco, CA 94080.
7
Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080.
8
Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA 94080.
9
Molecular Biology, Genentech, Inc., South San Francisco, CA 94080.
10
Biomolecular Imaging, Genentech, Inc., South San Francisco, CA 94080.
11
Safety Assessment, Genentech, Inc., South San Francisco, CA 94080.
12
Discovery Chemistry, Genentech, Inc., South San Francisco, CA 94080.
13
Division of Hematology, Department of Medicine, University of Colorado Cancer Center, Aurora, CO 80045.
14
Centre de Recherche en Cancérologie et Immunologie Nantes-Angers, INSERM, CNRS, Université d'Angers, Université de Nantes, BP 70721 Nantes, France.
15
Service d'Hématologie Clinique, Unité d'Investigation Clinique, Centre Hospitalier Universitaire, BP 70721 Nantes, France.
16
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143.
17
Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.
18
Cancer Immunology, Genentech, Inc., South San Francisco, CA 94080; aa@gene.com.

Abstract

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+ plasma cells while sparing CD138- cells derived from bone marrows of newly diagnosed or posttreatment-relapsed MM patients, in both US- and European Union-based cohorts. Effective IRE1α inhibition preserved glucose-induced insulin secretion by pancreatic microislets and viability of primary hepatocytes in vitro, as well as normal tissue homeostasis in mice. These results establish a strong rationale for developing kinase-directed inhibitors of IRE1α for MM therapy.

KEYWORDS:

endoplasmic reticulum stress; inositol-requiring enzyme 1; kinase inhibitors; multiple myeloma; unfolded protein response

Conflict of interest statement

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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