Disruption of IRE1α through its kinase domain attenuates multiple myeloma
| Autor: | Heidi J.A. Wallweber, Diego Acosta-Alvear, Yung-Chia Ariel Chen, Maria N. Lorenzo, Jiansheng Wu, Mark Merchant, Anna Shemorry, Michael J VanWyngarden, Klara Totpal, Jonathan M. Harnoss, Alvin Gogineni, Adrien Le Thomas, Daniel W. Sherbenou, Susan Kaufman, Robby M. Weimer, Marie-Gabrielle Braun, David A. Lawrence, Weiru Wang, Kevin R Clark, Mike Reichelt, Tom De Bruyn, Steven T Laing, Min Lu, Avi Ashkenazi, David Kan, Benjamin Haley, Jing Qing, Maureen Beresini, Justin Ly, Amy Heidersbach, Ehud Segal, Wendy Sandoval, Martine Amiot, Peter Walter, Scot A. Marsters, Patricia Gomez-Bougie, Dong Lee, Joachim Rudolph |
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| Přispěvatelé: | Department of Cancer Immunology, Genentech, Inc. [San Francisco], Translational Oncology [South San Francisco, CA, USA], Pathology [South San Francisco, CA, USA], Structural Biology [South San Francisco, CA, USA], Biochemical and Cellular Pharmacology [South San Francisco, CA, USA], Microchemistry, Proteomics and Lipidomics [South San Francisco, CA, USA], Protein Chemistry [South San Francisco, CA, USA], Drug Metabolism and Pharmacokinetics [South San Francisco, CA, USA], Molecular Biology [South San Francisco, CA, USA], Biomolecular Imaging [South San Francisco, CA, USA], Safety Assessment [South San Francisco, CA, USA], Department of Discovery Chemistry, Division of Hematology [Aurora, CO, USA] (Department of Medicine), University of Colorado Cancer Center [Aurora, CO, USA], Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service d'Hématologie Clinique [CHU Nantes] (Unité d'Investigation Clinique), Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Biochemistry and Biophysics [San Francisco], University of California, Howard Hughes Medical Institute [San Francisco, CA, USA], University of California [San Francisco] (UCSF), University of California-University of California, Bernardo, Elizabeth, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), University of California (UC), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC) |
| Rok vydání: | 2019 |
| Předmět: |
Male
X-Box Binding Protein 1 Chemokine Bortezomib Mice 0302 clinical medicine kinase inhibitors Lenalidomide Multiple myeloma media_common 0303 health sciences Multidisciplinary biology unfolded protein response Biological Sciences Middle Aged Protein-Serine-Threonine Kinases Endoplasmic Reticulum Stress 3. Good health Gene Expression Regulation Neoplastic multiple myeloma PNAS Plus 030220 oncology & carcinogenesis Female Antibody medicine.drug Signal Transduction inositol-requiring enzyme 1 [SDV.CAN]Life Sciences [q-bio]/Cancer Protein Serine-Threonine Kinases 03 medical and health sciences [SDV.CAN] Life Sciences [q-bio]/Cancer Endoribonucleases medicine media_common.cataloged_instance Animals Humans Secretion European union Protein Kinase Inhibitors 030304 developmental biology Aged Neoplastic business.industry Endoplasmic reticulum Cell Biology medicine.disease Xenograft Model Antitumor Assays Gene Expression Regulation Cancer research biology.protein business Homeostasis |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 116, iss 33 Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2019, pp.201906999. ⟨10.1073/pnas.1906999116⟩ Proceedings of the National Academy of Sciences of the United States of America, 2019, pp.201906999. ⟨10.1073/pnas.1906999116⟩ |
| ISSN: | 0027-8424 1091-6490 |
| DOI: | 10.1073/pnas.1906999116⟩ |
| Popis: | Significance Multiple myeloma (MM) is a lethal malignancy arising from plasma cells. MM cells experience endoplasmic reticulum (ER) stress due to immunoglobulin hyperproduction. The ER-resident sensor IRE1α mitigates ER stress by expanding protein-folding and secretion capacity, while supporting proteasomal degradation of ER misfolded proteins. IRE1α elaborates these functions by deploying a cytoplasmic kinase–RNase module to activate the transcription factor XBP1s. Although IRE1α has been implicated in MM, its validity as a potential therapeutic target—particularly as a kinase—has been unclear. Using genetic and pharmacologic disruption, we demonstrate that the IRE1α–XBP1s pathway is critical for MM tumor growth. We further show that the kinase domain of IRE1α is an effective and safe potential small-molecule target for MM therapy. 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. |
| Databáze: | OpenAIRE |
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