Venetoclax and dinaciclib elicit synergistic preclinical efficacy against hypodiploid acute lymphoblastic leukemia

Abstract

Hypodiploid acute lymphoblastic leukemia (ALL) is an aggressive blood cancer with a poor prognosis despite intensive chemotherapy or stem cell transplant. Children and adolescents with positive end-of-induction minimal residual disease (MRD) have an overall survival lower than 30%. However, data regarding therapeutic alternatives for this disease is nearly nonexistent, emphasizing the critical need for new or adjunctive therapies that can improve outcomes. We previously reported on the therapeutic efficacy of venetoclax (ABT-199) in hypodiploid B-ALL but with limitations as monotherapy. In this study, we set out to identify drugs enhancing the anti-leukemic effect of venetoclax in hypodiploid ALL. Using a high throughput drug screen, we identified dinaciclib, a cyclin-dependent kinase (CDK) inhibitor that worked synergistically with venetoclax to induce cell death in hypodiploid cell lines. This combination eradicated leukemic blasts within hypodiploid ALL PDX mice with low off-target toxicity. Our findings suggest that dual inhibition of BCL-2 (venetoclax) and CDK9/MCL-1 (dinaciclib) is a promising therapeutic approach in hypodiploid ALL, warranting further investigation to inform clinical trials in this high-risk patient population.

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

“…In particular, Zhou et al [64] found synergic effect of flavopiridol combined with a BCL-2 inhibitor in MM cells and Rello-Varona et al [32] found a high apoptosis induction by combination of dinaciclib with an inhibitor of BCL-X L in soft-tissue sarcomas. The combination of dinaciclib with ABT-199 has also been proposed against acute lymphocytic leukemia [65].…”

“…[32] found a high apoptosis induction by combination of dinaciclib with an inhibitor of BCL‐X L in soft‐tissue sarcomas. The combination of dinaciclib with ABT‐199 has also been proposed against acute lymphocytic leukemia [65].…”

Recent Updates in Venetoclax Combination Therapies in Pediatric Hematological Malignancies

“…There are reports suggesting that BH-3 mimetics are not sufficient in the treatment of childhood leukemias and combining BH-3 mimetics with inhibitors of survival pathways is not a dispensable option [98]. It was proven that the usage of VTX alone, despite a positive response, left leukemic blasts in the liver and spleen and positive minimal residual disease in the bone marrow of mice at the end of therapy [100]. Therefore, a substance that enhances the action of VTX was sought.…”

“…Therefore, a substance that enhances the action of VTX was sought. Researchers identified dinaciclib, which is an inhibitor of cyclin-dependent kinases 1, 2, 5, 9, and 16 showing synergy with VTX, obtaining a 97% inhibition of the growth of leukemic cells in hypodiploid ALL [100]. Such results are promising, but further research in this direction is needed.…”