학술논문
Dinaciclib synergizes with BH3 mimetics targeting BCL-2 and BCL-X L in multiple myeloma cell lines partially dependent on MCL-1 and in plasma cells from patients.
Document Type
Academic Journal
Author
Beltrán-Visiedo M; Apoptosis, Immunity & Cancer Group, IIS Aragón, University of Zaragoza, Spain.; Jiménez-Alduán N; Apoptosis, Immunity & Cancer Group, IIS Aragón, University of Zaragoza, Spain.; Díez R; Apoptosis, Immunity & Cancer Group, IIS Aragón, University of Zaragoza, Spain.; Hematology Service, Hospital Universitario Miguel Servet, Zaragoza, Spain.; Cuenca M; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, The Netherlands.; Benedi A; Apoptosis, Immunity & Cancer Group, IIS Aragón, University of Zaragoza, Spain.; Serrano-Del Valle A; Apoptosis, Immunity & Cancer Group, IIS Aragón, University of Zaragoza, Spain.; Azaceta G; Hematology Service, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain.; HCU-Lozano Blesa-Hematology Research Group, IIS Aragón, Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain.; Palomera L; Hematology Service, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain.; HCU-Lozano Blesa-Hematology Research Group, IIS Aragón, Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain.; Peperzak V; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, The Netherlands.; Anel A; Apoptosis, Immunity & Cancer Group, IIS Aragón, University of Zaragoza, Spain.; Naval J; Apoptosis, Immunity & Cancer Group, IIS Aragón, University of Zaragoza, Spain.; Marzo I; Apoptosis, Immunity & Cancer Group, IIS Aragón, University of Zaragoza, Spain.
Source
Publisher: John Wiley & Sons, Inc Country of Publication: United States NLM ID: 101308230 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-0261 (Electronic) Linking ISSN: 15747891 NLM ISO Abbreviation: Mol Oncol Subsets: MEDLINE
Subject
Language
English
Abstract
A better understanding of multiple myeloma (MM) biology has led to the development of novel therapies. However, MM is still an incurable disease and new pharmacological strategies are needed. Dinaciclib, a multiple cyclin-dependent kinase (CDK) inhibitor, which inhibits CDK1, 2, 5 and 9, displays significant antimyeloma activity as found in phase II clinical trials. In this study, we have explored the mechanism of dinaciclib-induced death and evaluated its enhancement by different BH3 mimetics in MM cell lines as well as in plasma cells from MM patients. Our results indicate a synergistic effect of dinaciclib-based combinations with B-cell lymphoma 2 or B-cell lymphoma extra-large inhibitors, especially in MM cell lines with partial dependence on myeloid cell leukemia sequence 1 (MCL-1). Simultaneous treatment with dinaciclib and BH3 mimetics ABT-199 or A-1155463 additionally showed a synergistic effect in plasma cells from MM patients, ex vivo. Altered MM cytogenetics did not affect dinaciclib response ex vivo, alone or in combined treatment, suggesting that these combinations could be a suitable therapeutic option for patients bearing cytogenetic alterations and poor prognosis. This work also opens the possibility to explore cyclin-dependent kinase 9 inhibition as a targeted therapy in MM patients overexpressing or with high dependence on MCL-1.
(© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
(© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)