Lysin (K)-Specific Demethylase 1 Inhibition Enhances Proteasome Inhibitor Response and Overcomes Drug Resistance in Multiple Myeloma
Author:
Bandini Cecilia1, Mereu Elisabetta1, Paradzik Tina1, Labrador Maria1, Maccagno Monica1, Cumerlato Michela1, Oreglia Federico1, Prever Lorenzo1, Manicardi Veronica2, Taiana Elisa3, Ronchetti Domenica3, D'Agostino Mattia1, Gay Francesca1, Larocca Alessandra1, Merlo Giorgio1, Hirsch Emilio1, Ciarrocchi Alessia2, Inghirami Giorgio4, Neri Antonino2, Piva Roberto1
Affiliation:
1. University of Turin 2. Azienda USL-IRCCS Reggio Emilia 3. University of Milan 4. Cornell University
Abstract
Abstract
Background Multiple myeloma (MM) is an incurable plasma cell malignancy, accounting for approximately 1% of all cancers. Despite recent advances in the treatment of MM, due to the introduction of proteasome inhibitors (PIs) such as bortezomib (BTZ) and carfilzomib (CFZ), relapses and disease progression remain common. Therefore, a major challenge is the development of novel therapeutic approaches to overcome drug resistance, improve patient outcomes, and broaden PIs applicability to other pathologies.Methods We performed genetic and drug screens to identify new synthetic lethal partners to PIs, and validated candidates in PI-sensitive and -resistant MM cells. We also tested best synthetic lethal interactions in other B-cell malignancies, such as mantle cell, Burkitt’s and diffuse large B-cell lymphomas. We evaluated the toxicity of combination treatments in normal peripheral blood mononuclear cells (PBMCs) and bone marrow stromal cells (BMSCs). We confirmed the combo treatment’ synergistic effects ex vivo in primary CD138 + cells from MM patients, and in different MM xenograft models. We exploited RNA-sequencing and Reverse-Phase Protein Arrays (RPPA) to investigate the molecular mechanisms of the synergy.Results We identified lysine (K)-specific demethylase 1 (LSD1) as a top candidate whose inhibition can synergize with CFZ treatment. LSD1 silencing enhanced CFZ sensitivity in both PI-resistant and -sensitive MM cells, resulting in increased tumor cell death. Several LSD1 inhibitors (SP2509, SP2577, and CC-90011) triggered synergistic cytotoxicity in combination with different PIs in MM and other B-cell neoplasms. CFZ/SP2509 treatment exhibited a favorable cytotoxicity profile toward PBMCs and BMSCs. We confirmed the clinical potential of LSD1-proteasome inhibition in primary CD138 + cells of MM patients, and in MM xenograft models, leading to the inhibition of tumor progression. DNA damage response (DDR) and proliferation machinery were the most affected pathways by CFZ/SP2509 combo treatment, responsible for the anti-tumoral effects.Conclusions The present study preclinically demonstrated that LSD1 inhibition could provide a valuable strategy to enhance PI sensitivity and overcome drug resistance in MM patients and that this combination might be exploited for the treatment of other B-cell malignancies, thus extending the therapeutic impact of the project.
Publisher
Research Square Platform LLC
Reference68 articles.
1. Cancer statistics, 2023;Siegel RL;CA. Cancer J. Clin.,2023 2. A. J. Cowan et al., “Diagnosis and Management of Multiple Myeloma: A Review,” JAMA, vol. 327, no. 5, pp. 464–477, Feb. 2022. 3. Proteasome Inhibitor Drugs;Fricker LD;Annu. Rev. Pharmacol. Toxicol.,2020 4. A. Palumbo and K. Anderson, “Multiple Myeloma,” N. Engl. J. Med., vol. 364, no. 11, pp. 1046–1060, Mar. 2011. 5. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells;Obeng EA;Blood,2006
|
|