The HDAC and PI3K Dual Inhibitor CUDC-907 Synergistically Enhances the Antileukemic Activity of Venetoclax in Preclinical Models of Acute Myeloid Leukemia

Overview

Journal Haematologica

Specialty Hematology

Date 2020 Mar 14

PMID 32165486

Citations 22

Authors

Xinyu Li

Yongwei Su

Katie Hege

Gerard Madlambayan

Holly Edwards

Tristan Knight

Lisa Polin

Juiwanna Kushner

Sijana H Dzinic

Kathryn White

Jay Yang

Regan Miller

Guan Wang

Lijing Zhao

Yue Wang

Hai Lin

Jeffrey W Taub

Yubin Ge

Affiliations

Soon will be listed here.

Abstract

Venetoclax is a promising agent in the treatment of acute myeloid leukemia, though its antileukemic activity is limited to combination therapies. Mcl-1 downregulation, Bim upregulation, and DNA damage have been identified as potential ways to enhance venetoclax activity. In this study, we combine venetoclax with the dual PI3K and histone deacetylase inhibitor CUDC-907, which can downregulate Mcl-1, upregulate Bim, and induce DNA damage, as well as downregulate c-Myc. We establish that CUDC-907 and venetoclax synergistically induce apoptosis in acute myeloid leukemia cell lines and primary acute myeloid leukemia patient samples ex vivo. CUDC-907 downregulates CHK1, Wee1, RRM1, and c-Myc, which were found to play a role in venetoclax-induced apoptosis. Interestingly, we found that venetoclax treatment enhances CUDC-907-induced DNA damage potentially through inhibition of DNA repair. In vivo results show that CUDC-907 enhances venetoclax efficacy in an acute myeloid leukemia cell line derived xenograft mouse model, supporting the development of CUDC-907 in combination with venetoclax for the treatment of acute myeloid leukemia.

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