Abstract
Elderly and frail patients, diagnosed with acute myeloid leukemia (AML) and ineligible to undergo intensive treatment, have a dismal prognosis. The small molecule inhibitor volasertib induces a mitotic block via inhibition of polo-like kinase 1 and has shown remarkable anti-leukemic activity when combined with low-dose cytarabine. We have demonstrated that AML cells are highly vulnerable to cell death in mitosis yet manage to escape a mitotic block through mitotic slippage by sustained proteasome-dependent slow degradation of cyclin B. Therefore, we tested whether interfering with mitotic slippage through proteasome inhibition arrests and kills AML cells more efficiently during mitosis. We show that therapeutic doses of bortezomib block the slow degradation of cyclin B during a volasertib-induced mitotic arrest in AML cell lines and patient-derived primary AML cells. In a xenotransplant mouse model of human AML, mice receiving volasertib in combination with bortezomib showed superior disease control compared to mice receiving volasertib alone, highlighting the potential therapeutic impact of this drug combination.
Highlights
As a result of continuous therapeutic advances in recent decades, the prognosis of acute myeloid leukemia (AML) has improved for young and healthy individuals eligible for intensive therapy [1, 2]
We have demonstrated that AML cells are highly vulnerable to cell death in mitosis yet manage to escape a mitotic block through mitotic slippage by sustained proteasomedependent slow degradation of cyclin B
We address the question of whether slow cyclin B degradation, the main driver of mitotic slippage, can be targeted by proteasome inhibition to consolidate a mitotic block for AML therapy
Summary
As a result of continuous therapeutic advances in recent decades, the prognosis of acute myeloid leukemia (AML) has improved for young and healthy individuals eligible for intensive therapy [1, 2]. Small molecule inhibitors are becoming more and more important due to a remarkable power in disease control, comparably low side effects and good tolerability [10, 11]. The latter characteristics placed these agents into focus for use in elderly and frail patients, ineligible to undergo intensive treatment and suffering from aggressive diseases, such as AML. Targeting pololike kinase 1 (Plk1) is an efficient antimitotic treatment approach [12] with BI6727 (volasertib) demonstrating a striking effect in AML when combined with low-dose cytarabine [13]. While antimitotic drugs play only a negligible role in the treatment of myeloid neoplasias, volasertib, when combined with low-dose cytarabine, induced significantly better clinical outcomes in patients suffering from AML as compared to patients receiving low-dose cytarabine alone [13]
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