Authors
Utku Horzum, Herbert Oberacher, Margot Haun, Stephan Geley, Monica Roman-Trufero, Holger Auner, Agnieszka Martowicz, Gerold Untergasser, Eberhard Gunsilius, Wolfgang Willenbacher, Hamdullah Yanik, Gunes Esendagli, Dominik Wolf, Hesso Farhan
Published in
Signal transduction and targeted therapy. Volume 11. Issue 1. Jul 07, 2026. Epub Jul 07, 2026.
Abstract
Multiple myeloma (MM) is characterized by the production and secretion of large quantities of immunoglobulins, making this malignancy highly dependent on mechanisms that maintain cellular proteostasis. While significant clinical progress has been made by targeting the degradative branch of proteostasis, much less attention has been given to the biosynthetic branch. In this study, we demonstrated that inhibiting COPII-dependent endoplasmic reticulum (ER) export induces cell death in several MM cell lines and primary patient-derived cells. The induction of cell death was dependent on the secretory status of MM cells. Blocking ER export in secretory MM cells caused the accumulation of misfolded proteins, which activated ER-associated degradation (ERAD). Consequently, we observed an ERAD-dependent increase in the levels of free cytosolic amino acids and a subsequent activation of mTORC1 signaling. Simultaneously, we observed mitochondrial dysfunction. These alterations resulted in a mismatch between the increased energy demand due to mTORC1 activation, and the disrupted energy supply from mitochondrial impairment. This energetic imbalance results in homeostatic collapse and cell death of secretory MM cells. The therapeutic potential of the concept was demonstrated in two in vivo myeloma models. These findings suggest that the ER export machinery could be a promising therapeutic target in multiple myeloma.
PMID:
42409778
Bibliographic data and abstract were imported from PubMed on 13 Aug 2026.
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