2. Academic Validation
  3. c-Myc plays a critical role in the antileukemic activity of the Mcl-1-selective inhibitor AZD5991 in acute myeloid leukemia

c-Myc plays a critical role in the antileukemic activity of the Mcl-1-selective inhibitor AZD5991 in acute myeloid leukemia

  • Apoptosis. 2022 Aug 9. doi: 10.1007/s10495-022-01756-7.
Shuang Liu 1,  Xinan Qiao 1,  Shuangshuang Wu 1 2,  Yuqinq Gai 1,  Yongwei Su 3 4,  Holly Edwards 3 4,  Yue Wang 2,  Hai Lin 5,  Jeffrey W Taub 6 7 8,  Guan Wang 9,  Yubin Ge 10 11
Affiliations

Affiliations

  • 1 National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, P.R. China.
  • 2 Department of Pediatric Hematology and Oncology, The First Hospital of Jilin University, Changchun, China.
  • 3 Department of Oncology, Wayne State University School of Medicine, 421 E. Canfield, 48201, Detroit, MI, USA.
  • 4 Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
  • 5 Department of Hematology and Oncology, The First Hospital of Jilin University, Changchun, China.
  • 6 Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
  • 7 Division of Pediatric Hematology and Oncology, Department of Pediatrics, Children's Hospital of Michigan, Detroit, MI, USA.
  • 8 Central Michigan University College of Medicine, Mt. Pleasant, MI, USA.
  • 9 National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, P.R. China. [email protected].
  • 10 Department of Oncology, Wayne State University School of Medicine, 421 E. Canfield, 48201, Detroit, MI, USA. [email protected].
  • 11 Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA. [email protected].
PMID: 35943677 DOI: 10.1007/s10495-022-01756-7
Abstract

Acute myeloid leukemia (AML) is an aggressive disease with a low 5-year overall survival rate of 29.5%. Thus, more effective therapies are in need to prolong survival of AML patients. Mcl-1 is overexpressed in AML and is associated with poor prognosis, representing a promising therapeutic target. The oncoprotein c-Myc is also overexpressed in AML and is a significant prognostic factor. In addition, Mcl-1 is required for c-Myc induced AML, indicating that c-Myc-driven AML harbors a Mcl-1 dependency and co-targeting of Mcl-1 and c-Myc represents a promising strategy to eradicate AML. In this study, we investigated the role of c-Myc in the antileukemic activity of Mcl-1 selective inhibitor AZD5991 and the antileukemic activity of co-targeting of Mcl-1 and c-Myc in preclinical models of AML. We found that c-Myc protein levels negatively correlated with AZD5991 EC50s in AML cell lines and primary patient samples. AZD5991 combined with inhibition of c-Myc synergistically induced Apoptosis in AML cell lines and primary patient samples, and cooperatively targeted leukemia progenitor cells. AML cells with acquired resistance to AZD5991 were resensitized to AZD5991 when c-Myc was inhibited. The combination also showed promising and synergistic antileukemic activity in vitro against AML cell lines with acquired resistance to the main chemotherapeutic drug AraC and primary AML cells derived from a patient at relapse post chemotherapy. The oncoprotein c-Myc represents a potential biomarker of AZD5991 sensitivity and inhibition of c-Myc synergistically enhances the antileukemic activity of AZD5991 against AML.

Keywords

10058-F4; AZD5991; Acute myeloid leukemia; Mcl-1; c-Myc.

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