Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma
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 diseas...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-08-01
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| Series: | Experimental Hematology & Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40164-023-00434-x |
| _version_ | 1797453637803311104 |
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| author | Cecilia Bandini Elisabetta Mereu Tina Paradzik Maria Labrador Monica Maccagno Michela Cumerlato Federico Oreglia Lorenzo Prever Veronica Manicardi Elisa Taiana Domenica Ronchetti Mattia D’Agostino Francesca Gay Alessandra Larocca Lenka Besse Giorgio Roberto Merlo Emilio Hirsch Alessia Ciarrocchi Giorgio Inghirami Antonino Neri Roberto Piva |
| author_facet | Cecilia Bandini Elisabetta Mereu Tina Paradzik Maria Labrador Monica Maccagno Michela Cumerlato Federico Oreglia Lorenzo Prever Veronica Manicardi Elisa Taiana Domenica Ronchetti Mattia D’Agostino Francesca Gay Alessandra Larocca Lenka Besse Giorgio Roberto Merlo Emilio Hirsch Alessia Ciarrocchi Giorgio Inghirami Antonino Neri Roberto Piva |
| author_sort | Cecilia Bandini |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T15:25:43Z |
| format | Article |
| id | doaj.art-d501676facca4dc6a35067bb270cd0fa |
| institution | Directory Open Access Journal |
| issn | 2162-3619 |
| language | English |
| last_indexed | 2024-03-09T15:25:43Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Experimental Hematology & Oncology |
| spelling | doaj.art-d501676facca4dc6a35067bb270cd0fa2023-11-26T12:33:09ZengBMCExperimental Hematology & Oncology2162-36192023-08-0112111710.1186/s40164-023-00434-xLysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myelomaCecilia Bandini0Elisabetta Mereu1Tina Paradzik2Maria Labrador3Monica Maccagno4Michela Cumerlato5Federico Oreglia6Lorenzo Prever7Veronica Manicardi8Elisa Taiana9Domenica Ronchetti10Mattia D’Agostino11Francesca Gay12Alessandra Larocca13Lenka Besse14Giorgio Roberto Merlo15Emilio Hirsch16Alessia Ciarrocchi17Giorgio Inghirami18Antonino Neri19Roberto Piva20Department of Molecular Biotechnology and Health Sciences, University of TurinDepartment of Molecular Biotechnology and Health Sciences, University of TurinDepartment of Molecular Biotechnology and Health Sciences, University of TurinDepartment of Molecular Biotechnology and Health Sciences, University of TurinDepartment of Molecular Biotechnology and Health Sciences, University of TurinDepartment of Molecular Biotechnology and Health Sciences, University of TurinDepartment of Molecular Biotechnology and Health Sciences, University of TurinDepartment of Molecular Biotechnology and Health Sciences, University of TurinLaboratory of Translational Research, Azienda USL-IRCCS Reggio EmiliaHematology, Fondazione Cà Granda IRCCS PoliclinicoHematology, Fondazione Cà Granda IRCCS PoliclinicoDepartment of Molecular Biotechnology and Health Sciences, University of TurinDepartment of Molecular Biotechnology and Health Sciences, University of TurinDepartment of Molecular Biotechnology and Health Sciences, University of TurinExperimental Oncology and Hematology, Department of Oncology and Hematology, St. Gallen Cantonal HospitalDepartment of Molecular Biotechnology and Health Sciences, University of TurinDepartment of Molecular Biotechnology and Health Sciences, University of TurinLaboratory of Translational Research, Azienda USL-IRCCS Reggio EmiliaDepartment of Biology, Faculty of Medicine, Masaryk UniversityDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Molecular Biotechnology and Health Sciences, University of TurinAbstract 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.https://doi.org/10.1186/s40164-023-00434-xMultiple myelomaB-cell neoplasmsProteasome inhibitorsSynthetic lethalityLSD1Drug resistance |
| spellingShingle | Cecilia Bandini Elisabetta Mereu Tina Paradzik Maria Labrador Monica Maccagno Michela Cumerlato Federico Oreglia Lorenzo Prever Veronica Manicardi Elisa Taiana Domenica Ronchetti Mattia D’Agostino Francesca Gay Alessandra Larocca Lenka Besse Giorgio Roberto Merlo Emilio Hirsch Alessia Ciarrocchi Giorgio Inghirami Antonino Neri Roberto Piva Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma Experimental Hematology & Oncology Multiple myeloma B-cell neoplasms Proteasome inhibitors Synthetic lethality LSD1 Drug resistance |
| title | Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma |
| title_full | Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma |
| title_fullStr | Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma |
| title_full_unstemmed | Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma |
| title_short | Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma |
| title_sort | lysin k specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma |
| topic | Multiple myeloma B-cell neoplasms Proteasome inhibitors Synthetic lethality LSD1 Drug resistance |
| url | https://doi.org/10.1186/s40164-023-00434-x |
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