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Ferrata Storti Foundation
Acute Myeloid Leukemia
The HDAC and PI3K dual inhibitor CUDC-907 synergistically enhances the antileukemic activity of venetoclax in preclinical models of acute myeloid leukemia
Haematologica 2021 Volume 106(5):1262-1277
Xinyu Li,1 Yongwei Su,1 Katie Hege,2 Gerard Madlambayan,3 Holly Edwards,4,5 Tristan Knight,6,7 Lisa Polin,4,5 Juiwanna Kushner,4 Sijana H. Dzinic,4,5
Kathryn White,4 Jay Yang,4 Regan Miller,3 Guan Wang,1 Lijing Zhao,8
Yue Wang,9 Hai Lin,10 Jeffrey W. Taub6,7 and Yubin Ge4,5,7
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; 2Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI, USA; 3Department of Biological Sciences, Oakland University, Rochester, MI, USA; 4Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; 5Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA; 6Division of Pediatric Hematology/Oncology, Department of Pediatrics, Children’s Hospital of Michigan, Detroit, MI, USA; 7Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA; 8Department of Rehabilitation, School of Nursing, Jilin University, Changchun, P.R. China; 9Department of Pediatric Hematology and Oncology, The First Hospital of Jilin University, Changchun, P.R. China and 10Department of Hematology and Oncology, The First Hospital of Jilin University, Changchun, P.R. China
1
ABSTRACT
Venetoclax is a promising agent in the treatment of acute myeloid leukemia (AML), though its antileukemic activity is limited to com- bination 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 his- tone 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 apopto- sis in AML cell lines and primary AML 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 find that veneto- clax 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 AML cell line derived xenograft mouse model, supporting the development of CUDC-907 in combination with venetoclax for the treatment of AML.
Introduction
Venetoclax (ABT-199) is an oral, selective Bcl-2 inhibitor that was approved by the Food and Drug Administration (FDA) in November 2018 for use in acute myeloid leukemia (AML) patients aged 75 or over, or for whom has comorbidities which preclude the use of intensive induction chemotherapy, in combination with azacitidine or decitabine (hypomethylating agents), or low-dose cytarabine. We recently reported a reduction in Bcl-2/Bim binding in the presence of veneto- clax and a resultant increase in the interaction between Bim and Mcl-1, especially in venetoclax-resistant AML models – a change which facilitates apoptotic eva- sion.1,2 Selective Mcl-1 inhibition appears sufficient to overcome this evasion.2,3 Triggering of DNA damage results in downregulation of Mcl-1, with functionally the same results (e.g., a relative excess of pro-apoptotic Bim in relation to the anti- apoptotic Mcl-1 and Bcl-2).4,5 We also found that Bcl-2 inhibition with venetoclax
Correspondence:
YUBIN GE
gey@karmanos.org
Received: July 25, 2019. Accepted: March 11, 2020. Pre-published: March 12, 2020.
https://doi.org/10.3324/haematol.2019.233445
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