Antileukemic activity and mechanism of action of the novel PI3K and histone deacetylase dual inhibitor CUDC-907 in acute myeloid leukemia
Xinyu Li,
Yongwei Su,
Gerard Madlambayan,
Holly Edwards,
Lisa Polin,
Juiwanna Kushner,
Sijana H. Dzinic,
Kathryn White,
Jun Ma,
Tristan Knight,
Guan Wang,
Yue Wang,
Jay Yang,
Jeffrey W. Taub,
Hai Lin,
Yubin Ge
Affiliations
Xinyu Li
National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, P.R. China
Yongwei Su
National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, P.R. China
Gerard Madlambayan
Department of Biological Sciences, Oakland University, Rochester, MI, USA
Holly Edwards
Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA;Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
Lisa Polin
Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA;Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
Juiwanna Kushner
Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA;Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
Sijana H. Dzinic
Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA;Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
Kathryn White
Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA;Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
Jun Ma
National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, P.R. China
Tristan Knight
Division of Pediatric Hematology/Oncology, Children’s Hospital of Michigan, Detroit, MI, USA;Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA
Guan Wang
National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, P.R. China
Yue Wang
Department of Pediatric Hematology and Oncology, The First Hospital of Jilin University, Changchun, P.R. China
Jay Yang
Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA
Jeffrey W. Taub
Division of Pediatric Hematology/Oncology, Children’s Hospital of Michigan, Detroit, MI, USA;Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA
Hai Lin
Department of Hematology and Oncology, The First Hospital of Jilin University, Changchun, P.R. China
Yubin Ge
Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA;Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA;Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA
Induction therapy for patients with acute myeloid leukemia (AML) has remained largely unchanged for over 40 years, while overall survival rates remain unacceptably low, highlighting the need for new therapies. The PI3K/Akt pathway is constitutively active in the majority of patients with AML. Given that histone deacetylase inhibitors have been shown to synergize with PI3K inhibitors in preclinical AML models, we investigated the novel dual-acting PI3K and histone deacetylase inhibitor CUDC-907 in AML cells both in vitro and in vivo. We demonstrated that CUDC-907 induces apoptosis in AML cell lines and primary AML samples and shows in vivo efficacy in an AML cell line-derived xenograft mouse model. CUDC-907-induced apoptosis was partially dependent on Mcl-1, Bim, and c-Myc. CUDC-907 induced DNA damage in AML cells while sparing normal hematopoietic cells. Downregulation of CHK1, Wee1, and RRM1, and induction of DNA damage also contributed to CUDC-907-induced apoptosis of AML cells. In addition, CUDC-907 treatment decreased leukemia progenitor cells in primary AML samples ex vivo, while also sparing normal hematopoietic progenitor cells. These findings support the clinical development of CUDC-907 for the treatment of AML.
