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@article{57367,
author = {Bandini, Cecilia and Mereu, Elisabetta and Paradzik, Tina and Labrador, Maria and Maccagno, Monica and Cumerlato, Michela and Oreglia, Federico and Prever, Lorenzo and Manicardi, Veronica and Taiana, Elisa and Ronchetti, Domenica and Agostino, Mattia and Gay, Francesca and Larocca, Alessandra and Bešše, Lenka and Merlo, Giorgio Roberto and Hirsch, Emilio and Ciarrocchi, Alessia and Inghirami, Giorgio and Neri, Antonino and Piva, Roberto},
article_location = {LONDON},
article_number = {1},
doi = {http://dx.doi.org/10.1186/s40164-023-00434-x},
keywords = {Multiple myeloma; B-cell neoplasms; Proteasome inhibitors; Synthetic lethality; LSD1; Drug resistance},
language = {eng},
issn = {2162-3619},
journal = {ONCOLOGY},
title = {Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma},
url = {https://ehoonline.biomedcentral.com/articles/10.1186/s40164-023-00434-x},
volume = {12},
year = {2023}
}
TY - JOUR
ID - 57367
AU - Bandini, Cecilia - Mereu, Elisabetta - Paradzik, Tina - Labrador, Maria - Maccagno, Monica - Cumerlato, Michela - Oreglia, Federico - Prever, Lorenzo - Manicardi, Veronica - Taiana, Elisa - Ronchetti, Domenica - Agostino, Mattia - Gay, Francesca - Larocca, Alessandra - Bešše, Lenka - Merlo, Giorgio Roberto - Hirsch, Emilio - Ciarrocchi, Alessia - Inghirami, Giorgio - Neri, Antonino - Piva, Roberto
PY - 2023
TI - Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma
JF - ONCOLOGY
VL - 12
IS - 1
SP - 1-17
EP - 1-17
PB - BMC
SN - 2162-3619
KW - Multiple myeloma
KW - B-cell neoplasms
KW - Proteasome inhibitors
KW - Synthetic lethality
KW - LSD1
KW - Drug resistance
UR - https://ehoonline.biomedcentral.com/articles/10.1186/s40164-023-00434-x
N2 - BackgroundMultiple 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.MethodsWe 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.ResultsWe 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.ConclusionsThe 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.
ER -
BANDINI, Cecilia, Elisabetta MEREU, Tina PARADZIK, Maria LABRADOR, Monica MACCAGNO, Michela CUMERLATO, Federico OREGLIA, Lorenzo PREVER, Veronica MANICARDI, Elisa TAIANA, Domenica RONCHETTI, Mattia AGOSTINO, Francesca GAY, Alessandra LAROCCA, Lenka BEŠŠE, Giorgio Roberto MERLO, Emilio HIRSCH, Alessia CIARROCCHI, Giorgio INGHIRAMI, Antonino NERI and Roberto PIVA. Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma. \textit{ONCOLOGY}. LONDON: BMC, 2023, vol.~12, No~1, p.~1-17. ISSN~2162-3619. Available from: https://dx.doi.org/10.1186/s40164-023-00434-x.
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