Proteasome inhibition enhances the efficacy of volasertib-induced mitotic arrest in AML in vitro and prolongs survival in vivo

// Dominik Schnerch 1 , Julia Schüler 2 , Marie Follo 1 , Julia Felthaus 1 , Dagmar Wider 1 , Kathrin Klingner 2 , Christine Greil 1 , Justus Duyster 1 , Monika Engelhardt 1 , Ralph Wäsch 1 1 Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany 2 Oncotest GmbH, Freiburg, Germany Correspondence to: Ralph Wäsch, email: ralph.waesch@uniklinik-freiburg.de Keywords: AML, antimitotic therapy, APC/C, mitotic slippage, proteasome inhibition Received: December 22, 2016 Accepted: February 07, 2017 Published: February 18, 2017 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.