Dinaciclib synergizes with BH3 mimetics targeting BCL-2 and BCL-XL in multiple myeloma cell lines partially-dependent on MCL-1 and in plasma cells from patients

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 anti-myeloma activity as found in Phase II clinical trials. In the present work, 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 (Bcl-2) or B-cell lymphoma extra-large (BCL-X_L ) 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 (CDK9) inhibition as a targeted therapy in MM patients overexpressing or with high dependence on Mcl-1.

BCL-2 proteins; BH3 mimetics; CDK inhibitors; cell death; multiple myeloma.