The HDAC and PI3K dual inhibitor CUDC-907 synergistically enhances the antileukemic activity of venetoclax in preclinical models of acute myeloid leukemia
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
Xinyu Li
School of Life Sciences, Jilin University, Changchun, China;
Yongwei Su
School of Life Sciences, Jilin University, Changchun, China;
Katie Hege
Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI, USA;
Gerard Madlambayan
Department of Biological Sciences, Oakland University, Rochester, MI, USA;
Holly Edwards
Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA;
Tristan Knight
Dept of Pediatrics, Children's Hospital of Michigan, Wayne State University, Detroit, MI, USA;
Lisa Polin
Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA;
Juiwanna Kushner
Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA;
Sijana H. Dzinic
Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA;
Kathryn White
Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA;
Jay Yang
Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA;
Regan Miller
Department of Biological Sciences, Oakland University, Rochester, MI, USA;
Guan Wang
School of Life Sciences, Jilin University, Changchun, China;
Lijing Zhao
Department of Rehabilitation, School of Nursing, Jilin University, Changchun, China;
Yue Wang
Dept. of Pediatric Hematology & Oncology, First Hospital of Jilin University, Changchun, China;
Hai Lin
Dept. of Hematology and Oncology, The First Hospital of Jilin University, Changchun, China;
Jeffrey W. Taub
Dept of Pediatrics, Children Hospital of Michigan, Wayne State University, Detroit, MI, USA;
Yubin Ge
Wayne State University School of Medicine, Detroit, MI, USA
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.
