Disruption of IRE1α through its kinase domain attenuates multiple myeloma

Multiple myeloma (MM) arises from malignant immunoglobulin-secreting plasma cells and remains an incurable, often lethal disease despite therapeutic advances. The unfolded-protein response sensor IRE1a supports protein secretion by deploying a kinase-endoribonuclease module to activate the transcription factor XBP1s. MM cells may coopt the IRE1a-XBP1s pathway; however, the validity of IRE1a as a potential MM therapeutic target is controversial. Genetic disruption of IRE1a or XBP1s, or pharmacologic IRE1a kinase inhibition, attenuated subcutaneous or orthometastatic growth of MM tumors in mice, and augmented efficacy of two established frontline antimyeloma agents, bortezomib or lenalidomide. Mechanistically, IRE1a perturbation inhibited expression of key components of the endoplasmic reticulum-associated degradation machinery, as well as secretion of immunoglobulin light chains and of cytokines and chemokines known to promote MM growth. Selective IRE1a kinase inhibition reduced viability of CD138⁺ plasma cells while sparing CD138^— cells derived from bone marrows of newly diagnosed or post-treatment relapsed MM patients, in both US- and EU-based cohorts. Effective IRE1a 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 IRE1a for MM therapy.