2. Academic Validation
  3. The Imipridone ONC213 Targets α-Ketoglutarate Dehydrogenase to Induce Mitochondrial Stress and Suppress Oxidative Phosphorylation in Acute Myeloid Leukemia

The Imipridone ONC213 Targets α-Ketoglutarate Dehydrogenase to Induce Mitochondrial Stress and Suppress Oxidative Phosphorylation in Acute Myeloid Leukemia

  • Cancer Res. 2024 Apr 1;84(7):1084-1100. doi: 10.1158/0008-5472.CAN-23-2659.
Yongwei Su 1 2 3,  Jenna L Carter 4 5,  Xinyu Li 3,  Yu Fukuda 6,  Ashley Gray 6 7,  John Lynch 6,  Holly Edwards 1 2,  Jun Ma 3,  Patrick Schreiner 8,  Lisa Polin 1 2,  Juiwanna Kushner 1 2,  Sijana H Dzinic 1 2,  Steven A Buck 9,  Shondra M Pruett-Miller 10 11,  Katie Hege-Hurrish 4,  Camenzind Robinson 12,  Xinan Qiao 3,  Shuang Liu 3,  Shuangshuang Wu 3,  Guan Wang 3,  Jing Li 1 2,  Joshua E Allen 13,  Varun V Prabhu 13,  Aaron D Schimmer 14,  Dhananjay Joshi 15,  Shiva Kalhor-Monfared 15,  Iain D G Watson 15,  Richard Marcellus 15,  Methvin B Isaac 15,  Rima Al-Awar 15 16,  Jeffrey W Taub 9 17,  Hai Lin 18,  John D Schuetz 6,  Yubin Ge 1 2 5
Affiliations

Affiliations

  • 1 Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.
  • 2 Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
  • 3 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.
  • 4 Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, Michigan.
  • 5 MD/PhD Program, Wayne State University School of Medicine, Detroit, Michigan.
  • 6 Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • 7 Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, Tennessee.
  • 8 Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • 9 Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, Michigan.
  • 10 Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • 11 Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • 12 St. Jude Children's Research Hospital Shared Imaging Resource, Memphis, Tennessee.
  • 13 Chimerix, Inc., Durham, North Carolina.
  • 14 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • 15 Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • 16 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
  • 17 Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan.
  • 18 Department of Hematology and Oncology, The First Hospital of Jilin University, Changchun, P.R. China.
PMID: 38266099 DOI: 10.1158/0008-5472.CAN-23-2659
Abstract

Eradication of acute myeloid leukemia (AML) is therapeutically challenging; many patients succumb to AML despite initially responding to conventional treatments. Here, we showed that the imipridone ONC213 elicits potent antileukemia activity in a subset of AML cell lines and primary patient samples, particularly in leukemia stem cells, while producing negligible toxicity in normal hematopoietic cells. ONC213 suppressed mitochondrial respiration and elevated α-ketoglutarate by suppressing α-ketoglutarate dehydrogenase (αKGDH) activity. Deletion of OGDH, which encodes αKGDH, suppressed AML fitness and impaired Oxidative Phosphorylation, highlighting the key role for αKGDH inhibition in ONC213-induced death. ONC213 treatment induced a unique mitochondrial stress response and suppressed de novo protein synthesis in AML cells. Additionally, ONC213 reduced the translation of MCL1, which contributed to ONC213-induced Apoptosis. Importantly, a patient-derived xenograft from a relapsed AML patient was sensitive to ONC213 in vivo. Collectively, these findings support further development of ONC213 for treating AML.

Significance: In AML cells, ONC213 suppresses αKGDH, which induces a unique mitochondrial stress response, and reduces MCL1 to decrease Oxidative Phosphorylation and elicit potent antileukemia activity. See related commentary by Boët and Sarry, p. 950.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-164515
    αKGDH Inhibitor