Abstract C047: Unraveling proteotoxic and oxidative stress - driven adaptations in multiple myeloma

Abstract Multiple Myeloma (MM) is a chronic hematologic malignancy characterized by gradual progression, recurrent episodes, and eventual resistance to existing therapies Despite advancements in understanding the cellular mechanisms underlying health-to-disease transitions, recurrence, and therapeutic response, critical aspects of MM pathology remain unexplored. To address these issues, our study focuses on the proteostasis network [PN; being composed, among others, from the endoplasmic reticulum unfolded protein response (UPR), molecular chaperones, the autophagy-lysosome (ALP) and the ubiquitin-proteasome (UPP) pathways], a critical regulator of proteome homeodynamics, often dysregulated in carcinogenesis, as well as on redox perturbations which influence the interplay between protein quality control and disease progression. To study the PN modules functionality in MM, we comparatively analyzed several MM cell lines representing distinct genetic backgrounds, versus a near normal B lymphocyte cell line. We observed an activation of UPP and ALP pathways in cancerous cells accompanied by an accumulation of ubiquitinated and aggregated proteins suggesting enhanced proteome instability and proteotoxic stress. Interestingly these molecular adaptations are accompanied by increased oxidative load in MM cells and altered metabolic status possibly to support their heightened bioenergetic and biosynthetic demands. Alongside standard assessments of PN functionality, a high-resolution proteomics analysis among the various MM cell lines revealed differential protein expression signatures in comparison to the control cell line. The most differentially regulated pathways in MM cells included proteostatic modules (e.g., UPP and ALP), as well as secretory, metabolic, and oxidative-stress pathways. By linking redox imbalances to proteostasis disruption and metabolic remodeling, our findings provide deeper insights into the molecular strategies that MM cells employ to sustain growth and survival, paving thus the way for improved therapeutic strategies targeting PN modules in this hematologic malignancy. Acknowledgments : We thank the ELMUMY Horizon Europe project. Funded by the European Union (Project 101097094 — ELMUMY). Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or HADEA. Neither the European Union nor the granting authority can be held responsible for them.” Citation Format: Despoina Gianniou, Eirini Gkogkou, Paraskevi Karousi, Julie Courraud, Jérôme Moreaux, Sentiljana Gumeni, Jerome Zoidakis, Guillaume Médard, Meletios-Athanasios Dimopoulos, Efstathios Kastritis, Ioannis Trougakos. Unraveling proteotoxic and oxidative stress - driven adaptations in multiple myeloma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C047.