Inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models of acute myeloid leukemia

Signal Transduction and Targeted Therapy
Daniel A LuedtkeYubin Ge

Abstract

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.

References

Feb 16, 2002·Methods : a Companion to Methods in Enzymology·K J Livak, T D Schmittgen
May 29, 2002·Oncogene·Shinichi KitadaJohn C Reed
Feb 3, 2005·Journal of the National Cancer Institute·Yubin GeJeffrey W Taub
Dec 18, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Aaron D SchimmerGautam Borthakur
Oct 5, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Chengzhi XieYubin Ge
Jun 1, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Matthew S Davids, Anthony Letai
Feb 2, 2013·Clinical and Translational Medicine·Lissa Nurrul Abdullah, Edward Kai-Hua Chow
Jun 7, 2014·Blood·Cyril Fauriat, Daniel Olive
Jan 9, 2016·CA: a Cancer Journal for Clinicians·Rebecca L SiegelAhmedin Jemal
Jan 15, 2016·Cell Cycle·Fatima Morales, Antonio Giordano
Apr 23, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Xiaojia NiuYubin Ge
Jul 1, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Angela NebbiosoLucia Altucci
Jan 2, 2018·Oncotarget·James BogenbergerRaoul Tibes
Feb 24, 2018·Journal of Experimental & Clinical Cancer Research : CR·Silvia BoffoAntonio Giordano
Jan 9, 2019·CA: a Cancer Journal for Clinicians·Rebecca L SiegelAhmedin Jemal
Mar 21, 2019·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Andrew H WeiGail J Roboz

❮ Previous
Next ❯

Citations

Nov 1, 2020·Blood Cancer Journal·Naval DaverCourtney D DiNardo
Dec 19, 2020·Signal Transduction and Targeted Therapy·Jenna L CarterYubin Ge

❮ Previous
Next ❯

Methods Mentioned

BETA
xenograft
flow cytometry
co-immunoprecipitation
immunoprecipitation
co-IP
PCR
Infrared Imaging
transfection
xenografts

Software Mentioned

CompuSyn
GraphPad Prism
Odyssey

Related Concepts

Related Feeds

Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease with approximately 20,000 cases per year in the United States. AML also accounts for 15-20% of all childhood acute leukemias, while it is responsible for more than half of the leukemic deaths in these patients. Here is the latest research on this disease.

B-Cell Leukemia (Keystone)

B-cell leukemia includes various types of lymphoid leukemia that affect B cells. Here is the latest research on B-cell leukemia.

AML: Role of LSD1 by CRISPR (Keystone)

Find the latest rersearrch on the ability of CRISPR-Cas9 mutagenesis to profile the interactions between lysine-specific histone demethylase 1 (LSD1) and chemical inhibitors in the context of acute myeloid leukemia (AML) here.