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Acute Myeloid Leukemia
Antileukemic activity and mechanism of action of the novel PI3K and histone deacetylase dual inhibitor CUDC-907 in acute myeloid leukemia
Ferrata Storti Foundation
Haematologica 2019 Volume 104(11):2225-2240
Xinyu Li,1# Yongwei Su,1# Gerard Madlambayan,2 Holly Edwards,3,4 Lisa Polin,3,4 Juiwanna Kushner,3,4 Sijana H. Dzinic,3,4 Kathryn White,3,4 Jun Ma,1 Tristan Knight,5,6 Guan Wang,1 Yue Wang,7 Jay Yang,3 Jeffrey W. Taub,5,6 Hai Lin,8 and Yubin Ge3,4,6
1National 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; 2Department of Biological Sciences, Oakland University, Rochester, MI, USA; 3Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; 4Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA; 5Division of Pediatric Hematology/Oncology, Children’s Hospital of Michigan, Detroit, MI, USA; 6Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA; 7Department of Pediatric Hematology and Oncology, The First Hospital of Jilin University, Changchun, P.R. China and 8Department of Hematology and Oncology, The First Hospital of Jilin University, Changchun, P.R. China
#XL and YS contributed equally to this work.
ABSTRACT
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 nor- mal hematopoietic cells. Downregulation of CHK1, Wee1, and RRM1, and induction of DNA damage also contributed to CUDC-907-induced apop- tosis 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 devel- opment of CUDC-907 for the treatment of AML.
Introduction
Acute myeloid leukemia (AML) is a myeloid malignancy characterized by increased self-renewal, limited differentiation, and deregulated proliferation of myeloid blasts.1 Little has changed in the treatment of AML over the past 40 years. Despite low overall 5-year survival rates (~25% for adults and ~65% for children)2, standard induction therapy for AML patients continues to consist of cytarabine and an anthracycline (e.g., daunorubicin) backbone. The major contributor to such low overall survival rates is resistance to chemotherapy. Leukemia-initiating cells are one population thought to be responsible for relapse. Due to the quiescent nature of leukemia-initiating cells, cur- rent chemotherapy is often incapable of fully eradicating all these cells.3 Therefore, new therapies that not only eliminate bulk leukemia cells but also eradicate leukemia- initiating cells are urgently needed to improve the overall survival rates of people with this deadly disease.
Correspondence:
YUBIN GE
gey@karmanos.org
HAI LIN
maillinhai@sina.com
Received: July 5, 2018.
Accepted: February 28, 2019. Pre-published: February 28, 2019.
doi:10.3324/haematol.2018.201343
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/11/2225
©2019 Ferrata Storti Foundation
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haematologica | 2019; 104(11)
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