131104 20241125101136.0 doi 10.1002/1878-0261.13522 sideral 136689 ART-2023-136689 eng Beltrán-Visiedo, Manuel Universidad de Zaragoza Dinaciclib synergizes with BH3 mimetics targeting BCL-2 and BCL-XL in multiple myeloma cell lines partially dependent on <scp>MCL</scp>-1 and in plasma cells from patients 2023 Access copy available to the general public Unrestricted 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. info:eu-repo/grantAgreement/ES/DGA/B31-20R info:eu-repo/grantAgreement/ES/MECD/FPU17-02586 info:eu-repo/grantAgreement/ES/MICINN/PID2019-105128RB-I00 info:eu-repo/grantAgreement/ES/MINECO/SAF2016-76338-R info:eu-repo/semantics/openAccess by http://creativecommons.org/licenses/by/3.0/es/ 5.0 2023 ONCOLOGY 67 / 322 = 0.208 2023 Q1 T1 1.94 2023 Cancer Research 2023 Q1 Genetics 2023 Q1 Oncology 2023 Q1 Molecular Medicine 2023 Q1 Medicine (miscellaneous) 2023 Q1 12.6 2023 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Jiménez-Alduán, Nelia Díez, Rosana Universidad de Zaragoza Cuenca, Marta Benedi, Andrea Universidad de Zaragoza Serrano-Del Valle, Alfonso Azaceta, Gemma Universidad de Zaragoza (orcid)0000-0001-5068-7355 Palomera, Luis Peperzak, Victor Anel, Alberto Universidad de Zaragoza (orcid)0000-0002-5175-8394 Naval, Javier Universidad de Zaragoza (orcid)0000-0003-2156-8378 Marzo, Isabel Universidad de Zaragoza (orcid)0000-0002-2315-9079 1007 610 Universidad de Zaragoza Dpto. Medicina, Psiqu. y Derm. Area Medicina 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 1002 050 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Biología Celular 17, 12 (2023), 2507-2525 Molecular Oncology Molecular Oncology 1574-7891 2692771 http://zaguan.unizar.es/record/131104/files/texto_completo.pdf Versión publicada 2536561 http://zaguan.unizar.es/record/131104/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:131104 articulos driver 2024-11-22-12:00:59 ARTICLE