000131104 001__ 131104 000131104 005__ 20241125101136.0 000131104 0247_ $$2doi$$a10.1002/1878-0261.13522 000131104 0248_ $$2sideral$$a136689 000131104 037__ $$aART-2023-136689 000131104 041__ $$aeng 000131104 100__ $$aBeltrán-Visiedo, Manuel$$uUniversidad de Zaragoza 000131104 245__ $$aDinaciclib synergizes with BH3 mimetics targeting BCL-2 and BCL-XL in multiple myeloma cell lines partially dependent on <scp>MCL</scp>-1 and in plasma cells from patients 000131104 260__ $$c2023 000131104 5060_ $$aAccess copy available to the general public$$fUnrestricted 000131104 5203_ $$aA better understanding of multiple myeloma (MM) biology has led to the development of novel therapies. However, MM is still an incurable disease and new pharmacological strategies are needed. Dinaciclib, a multiple cyclin‐dependent kinase (CDK) inhibitor, which inhibits CDK1, 2, 5 and 9, displays significant antimyeloma activity as found in phase II clinical trials. In this study, we have explored the mechanism of dinaciclib‐induced death and evaluated its enhancement by different BH3 mimetics in MM cell lines as well as in plasma cells from MM patients. Our results indicate a synergistic effect of dinaciclib‐based combinations with B‐cell lymphoma 2 or B‐cell lymphoma extra‐large inhibitors, especially in MM cell lines with partial dependence on myeloid cell leukemia sequence 1 (MCL‐1). Simultaneous treatment with dinaciclib and BH3 mimetics ABT‐199 or A‐1155463 additionally showed a synergistic effect in plasma cells from MM patients, ex vivo. Altered MM cytogenetics did not affect dinaciclib response ex vivo, alone or in combined treatment, suggesting that these combinations could be a suitable therapeutic option for patients bearing cytogenetic alterations and poor prognosis. This work also opens the possibility to explore cyclin‐dependent kinase 9 inhibition as a targeted therapy in MM patients overexpressing or with high dependence on MCL‐1. 000131104 536__ $$9info:eu-repo/grantAgreement/ES/DGA/B31-20R$$9info:eu-repo/grantAgreement/ES/MECD/FPU17-02586$$9info:eu-repo/grantAgreement/ES/MICINN/PID2019-105128RB-I00$$9info:eu-repo/grantAgreement/ES/MINECO/SAF2016-76338-R 000131104 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/ 000131104 590__ $$a5.0$$b2023 000131104 592__ $$a1.94$$b2023 000131104 591__ $$aONCOLOGY$$b67 / 322 = 0.208$$c2023$$dQ1$$eT1 000131104 593__ $$aCancer Research$$c2023$$dQ1 000131104 593__ $$aGenetics$$c2023$$dQ1 000131104 593__ $$aOncology$$c2023$$dQ1 000131104 593__ $$aMolecular Medicine$$c2023$$dQ1 000131104 593__ $$aMedicine (miscellaneous)$$c2023$$dQ1 000131104 594__ $$a12.6$$b2023 000131104 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000131104 700__ $$aJiménez-Alduán, Nelia 000131104 700__ $$aDíez, Rosana$$uUniversidad de Zaragoza 000131104 700__ $$aCuenca, Marta 000131104 700__ $$aBenedi, Andrea$$uUniversidad de Zaragoza 000131104 700__ $$aSerrano-Del Valle, Alfonso 000131104 700__ $$0(orcid)0000-0001-5068-7355$$aAzaceta, Gemma$$uUniversidad de Zaragoza 000131104 700__ $$aPalomera, Luis 000131104 700__ $$aPeperzak, Victor 000131104 700__ $$0(orcid)0000-0002-5175-8394$$aAnel, Alberto$$uUniversidad de Zaragoza 000131104 700__ $$0(orcid)0000-0003-2156-8378$$aNaval, Javier$$uUniversidad de Zaragoza 000131104 700__ $$0(orcid)0000-0002-2315-9079$$aMarzo, Isabel$$uUniversidad de Zaragoza 000131104 7102_ $$11007$$2610$$aUniversidad de Zaragoza$$bDpto. Medicina, Psiqu. y Derm.$$cArea Medicina 000131104 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole. 000131104 7102_ $$11002$$2050$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Biología Celular 000131104 773__ $$g17, 12 (2023), 2507-2525$$pMolecular Oncology$$tMolecular Oncology$$x1574-7891 000131104 8564_ $$s2692771$$uhttps://zaguan.unizar.es/record/131104/files/texto_completo.pdf$$yVersión publicada 000131104 8564_ $$s2536561$$uhttps://zaguan.unizar.es/record/131104/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000131104 909CO $$ooai:zaguan.unizar.es:131104$$particulos$$pdriver 000131104 951__ $$a2024-11-22-12:00:59 000131104 980__ $$aARTICLE