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

Article

Author: Hege-Hurrish, Katie ; Carter, Jenna L. ; Su, Yongwei ; Schreiner, Patrick ; Edwards, Holly ; Li, Xinyu ; Pruett-Miller, Shondra M. ; Lynch, John ; Marcellus, Richard ; Dzinic, Sijana H. ; Lin, Hai ; Schimmer, Aaron D. ; Allen, Joshua E. ; Ma, Jun ; Fukuda, Yu ; Liu, Shuang ; Li, Jing ; Polin, Lisa ; Schuetz, John D. ; Qiao, Xinan ; Ge, Yubin ; Wang, Guan ; Kushner, Juiwanna ; Joshi, Dhananjay ; Isaac, Methvin B. ; Wu, Shuangshuang ; Watson, Iain D. G. ; Al-awar, Rima ; Kalhor-Monfared, Shiva ; Prabhu, Varun V. ; Gray, Ashley ; Robinson, Camenzind ; Taub, Jeffrey W. ; Buck, Steven A.

AbstractEradication 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

01 Apr 2024·Cancer Research

Targeting Metabolic Dependencies Fueling the TCA Cycle to Circumvent Therapy Resistance in Acute Myeloid Leukemia

Article

Author: Boët, Emeline ; Sarry, Jean-Emmanuel

AbstractAcute myeloid leukemia (AML) is one of the most prevalent blood cancers, characterized by a dismal survival rate. This poor outcome is largely attributed to AML cells that persist despite treatment and eventually result in relapse. Relapse-initiating cells exhibit diverse resistance mechanisms, encompassing genetic factors and, more recently discovered, nongenetic factors such as metabolic adaptations. Leukemic stem cells (LSC) rely on mitochondrial metabolism for their survival, whereas hematopoietic stem cells primarily depend on glycolysis. Furthermore, following treatments such as cytarabine, a standard in AML treatment for over four decades, drug-persisting leukemic cells exhibit an enhanced reliance on mitochondrial metabolism. In this issue of Cancer Research, two studies investigated dependencies of AML cells on two respiratory substrates, α-ketoglutarate and lactate-derived pyruvate, that support mitochondrial oxidative phosphorylation (OXPHOS) following treatment with the imipridone ONC-213 and the BET inhibitor INCB054329, respectively. Targeting lactate utilization by interfering with monocarboxylate transporter 1 (MCT1 or SLC16A1) or lactate dehydrogenase effectively sensitized cells to BET inhibition in vitro and in vivo. In addition, ONC-213 affected αKGDH, a pivotal NADH-producing enzyme of the TCA cycle, to induce a mitochondrial stress response through ATF4 activation that diminished the expression of the antiapoptotic protein MCL1, consequently promoting apoptosis of AML cells. In summary, targeting these mitochondrial dependencies might be a promising strategy to kill therapy-naïve and treatment-resistant OXPHOS-reliant LSCs and to delay or prevent relapse.See related articles by Monteith et al., p. 1101 and Su et al., p. 1084

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Preclinical	US	Wayne State University School of Medicine	-
Acute Myeloid Leukemia	Preclinical	CN	Jilin University	-

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