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
  • 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.
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.

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