Volume 5 Issue 1, Mar 2020

ISSN: 2095-9907 

EISSN: 2059-23635 

2023 impact factor 40.8 

 (Clarivate Analytics, 2024)
Volume 5 Issue 1, Mar 2020:
Article
Inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models of acute myeloid leukemia
Daniel A. Luedtke,Yongwei Su,Jun Ma,Xinyu Li,Steven A. Buck,Holly Edwards,Lisa Polin,Juiwanna Kushner,Sijana H. Dzinic,Kathryn White,Hai Lin,Jeffrey W. Taub &…Yubin Ge  ORCID: orcid.org/0000-0002-8748-716X 
Venetoclax, an FDA-approved Bcl-2 selective inhibitor for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia (AML), is tolerated well in elderly patients with AML and has good overall response rates; however, resistance remains a concern. In this study, we show that targeting CDK9 with voruciclib in combination with venetoclax results in synergistic antileukemic activity against AML cell lines and primary patient samples. CDK9 inhibition enhances venetoclax activity through downregulation of Mcl-1 and c-Myc. However, downregulation of Mcl-1 is transient, which necessitates an intermittent treatment schedule to allow for repeated downregulation of Mcl-1. Accordingly, an every other day schedule of the CDK9 inhibitor is effective in vitro and in vivo in enhancing the efficacy of venetoclax. Our preclinical data provide a rationale for an intermittent drug administration schedule for the clinical evaluation of the combination treatment for AML.