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Disruption of IRE1α through its Kinase Domain Attenuates Multiple Myeloma

Jonathan M Harnoss, Adrien Le Thomas, Scot A Marsters, David A Lawrence, Min Lu, Yung-Chia Ariel Chen, Jing Qing, Klara Totpal, David Kan, Ehud Segal, Heidi Ackerly Wallweber, Weiru Wang, Kevin Clark, Susan Kaufman, Maureen Beresini, Wendy Sandoval, Maria Lorenzo, Jiansheng Wu, Justin Ly, Tom De Bruyn, Amy Heidersbach, Benjamin Haley, Alvin Gogineni, Robby Weimer, Dong Lee, Marie-Gabrielle Braun, Joachim Rudolph, Michael J VanWyngarden, Daniel W Sherbenou, Patricia Gomez-Bougie, Martine Amiot, Diego Acosta-Alvear, Peter Walter, Avi Ashkenazi
doi: https://doi.org/10.1101/495242
Jonathan M Harnoss
aCancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 USA
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Adrien Le Thomas
aCancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 USA
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Scot A Marsters
aCancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 USA
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David A Lawrence
aCancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 USA
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Min Lu
aCancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 USA
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Yung-Chia Ariel Chen
aCancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 USA
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Jing Qing
aCancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 USA
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Klara Totpal
bTranslational Oncology, 1 DNA Way, South San Francisco, CA 94080 USA
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David Kan
bTranslational Oncology, 1 DNA Way, South San Francisco, CA 94080 USA
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Ehud Segal
bTranslational Oncology, 1 DNA Way, South San Francisco, CA 94080 USA
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Heidi Ackerly Wallweber
cStructural Biology, 1 DNA Way, South San Francisco, CA 94080 USA
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Weiru Wang
cStructural Biology, 1 DNA Way, South San Francisco, CA 94080 USA
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Kevin Clark
dBiochemical and Cellular Pharmacology, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080 USA
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Susan Kaufman
dBiochemical and Cellular Pharmacology, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080 USA
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Maureen Beresini
dBiochemical and Cellular Pharmacology, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080 USA
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Wendy Sandoval
eMicrochemistry, Proteomics and Lipidomics, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080 USA
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Maria Lorenzo
fProtein Chemistry, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080 USA
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Jiansheng Wu
fProtein Chemistry, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080 USA
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Justin Ly
gDrug Metabolism and Pharmacokinetics, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080 USA
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Tom De Bruyn
gDrug Metabolism and Pharmacokinetics, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080 USA
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Amy Heidersbach
hMolecular Biology, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080 USA
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Benjamin Haley
hMolecular Biology, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080 USA
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Alvin Gogineni
iBiomolecular Imaging, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080 USA
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Robby Weimer
iBiomolecular Imaging, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080 USA
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Dong Lee
jSafety Assessment, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080 USA
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Marie-Gabrielle Braun
kDiscovery Chemistry, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080 USA
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Joachim Rudolph
kDiscovery Chemistry, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080 USA
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Michael J VanWyngarden
lDivision of Hematology, Department of Medicine, University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora CO 80045 USA
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Daniel W Sherbenou
lDivision of Hematology, Department of Medicine, University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora CO 80045 USA
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Patricia Gomez-Bougie
mCRCINA, INSERM, CNRS, Université d’Angers, Université de Nantes, Nantes, BP 70721, France
nService d’Hématologie Clinique, Unité d’Investigation Clinique, CHU, Nantes, BP 70721 France
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Martine Amiot
mCRCINA, INSERM, CNRS, Université d’Angers, Université de Nantes, Nantes, BP 70721, France
nService d’Hématologie Clinique, Unité d’Investigation Clinique, CHU, Nantes, BP 70721 France
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Diego Acosta-Alvear
oDepartment of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94143 USA
pHoward Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94143 USA
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Peter Walter
oDepartment of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94143 USA
pHoward Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94143 USA
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Avi Ashkenazi
aCancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 USA
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  • For correspondence: aa@gene.com
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Abstract

Multiple myeloma (MM) arises from malignant immunoglobulin-secreting plasma cells and remains an incurable, often lethal disease despite recent 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 coopt the IRE1α-XBP1s pathway; however, the validity of IRE1α as a potential MM therapeutic target is controversial. Here we show that 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 well-established frontline antimyeloma agents, bortezomib or lenalidomide. Mechanistically, IRE1α perturbation inhibited expression of key components of the ER-associated degradation machinery, as well as cytokines and chemokines known to promote MM growth. Selective IRE1α kinase inhibition reduced viability of CD138+ plasma cells while sparing CD138− cells from bone marrow of newly diagnosed MM patients or patients whose disease relapsed after 1 - 4 lines of treatment in both US- and EU-based cohorts. IRE1α inhibition preserved survival and glucose-induced insulin secretion by pancreatic microislets. Together, these results establish a strong therapeutic rationale for targeting IRE1α with kinase-based small-molecule inhibitors in MM.

Significance statement Multiple myeloma (MM) is a lethal malignancy of plasma cells. MM cells have an expanded endoplasmic reticulum (ER) that is constantly under stress due to immunoglobulin hyperproduction. The ER-resident sensor IRE1α mitigates ER stress by expanding the ER’s protein-folding capacity while supporting proteasomal degradation of misfolded ER proteins. IRE1α elaborates these functions by deploying its cytoplasmic kinase-RNase module to activate the transcription factor XBP1s. The validity of IRE1α as a potential therapeutic target in MM has been questioned. Using genetic and pharmacologic disruption in vitro and in vivo, we demonstrate that the IRE1α-XBP1s pathway plays a critical role in MM growth. We further show that IRE1α’s kinase domain is an effective and safe potential small-molecule target for MM therapy.

Footnotes

  • Minor typo - author list

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Disruption of IRE1α through its Kinase Domain Attenuates Multiple Myeloma
Jonathan M Harnoss, Adrien Le Thomas, Scot A Marsters, David A Lawrence, Min Lu, Yung-Chia Ariel Chen, Jing Qing, Klara Totpal, David Kan, Ehud Segal, Heidi Ackerly Wallweber, Weiru Wang, Kevin Clark, Susan Kaufman, Maureen Beresini, Wendy Sandoval, Maria Lorenzo, Jiansheng Wu, Justin Ly, Tom De Bruyn, Amy Heidersbach, Benjamin Haley, Alvin Gogineni, Robby Weimer, Dong Lee, Marie-Gabrielle Braun, Joachim Rudolph, Michael J VanWyngarden, Daniel W Sherbenou, Patricia Gomez-Bougie, Martine Amiot, Diego Acosta-Alvear, Peter Walter, Avi Ashkenazi
bioRxiv 495242; doi: https://doi.org/10.1101/495242
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Disruption of IRE1α through its Kinase Domain Attenuates Multiple Myeloma
Jonathan M Harnoss, Adrien Le Thomas, Scot A Marsters, David A Lawrence, Min Lu, Yung-Chia Ariel Chen, Jing Qing, Klara Totpal, David Kan, Ehud Segal, Heidi Ackerly Wallweber, Weiru Wang, Kevin Clark, Susan Kaufman, Maureen Beresini, Wendy Sandoval, Maria Lorenzo, Jiansheng Wu, Justin Ly, Tom De Bruyn, Amy Heidersbach, Benjamin Haley, Alvin Gogineni, Robby Weimer, Dong Lee, Marie-Gabrielle Braun, Joachim Rudolph, Michael J VanWyngarden, Daniel W Sherbenou, Patricia Gomez-Bougie, Martine Amiot, Diego Acosta-Alvear, Peter Walter, Avi Ashkenazi
bioRxiv 495242; doi: https://doi.org/10.1101/495242

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