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.
- 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.
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.