Targeting mitochondrial respiration for the treatment of acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease with variable presentation, molecular phenotype, and cytogenetic abnormalities and has seen very little improvement in patient survival over the last few decades. This heterogeneity supports poor prognosis partially through the variability in response to the standard chemotherapy. Further understanding of molecular heterogeneity has promoted the development of novel treatments, some of which target mitochondrial metabolism and function. This review discusses the relative dependency that AML cells have on mitochondrial function, and the ability to pivot this reliance to target important subsets of AML cells, including leukemia stem cells (LSCs). LSCs are tumor-initiating cells that are resistant to standard chemotherapy and promote the persistence and relapse of AML. Historically, LSCs have been targeted based on immunophenotype, but recent developments in the understanding of LSC metabolism has demonstrated unique abilities to target LSCs while sparing normal hematopoietic stem cells (HSCs) through inhibition of mitochondrial function. Here we highlight the use of small molecules that have been demonstrated to effectively target mitochondrial function. IACS-010759 and ME-344 target the electron transport chain (ETC) to inhibit oxidative phosphorylation (OXPHOS). The imipridone family (ONC201, ONC206, ONC212) of inhibitors target mitochondria through activation of ClpP mitochondrial protease and reduce function of essential pathways. These molecules offer a new mechanism for developing clinical therapies in AML and support novel strategies to target LSCs in parallel with conventional therapies.

Keywords: Acute myeloid leukemia; IACS-010759; ME-344; Mitochondria; ONC201; Oxidative phosphorylation.

Fig. 1.

Hematopoietic stem cell and leukemia stem cell metabolism [38,39]. Normal hematopoietic stem cells (HSCs) are more dependent on glycolysis over OXPHOS to support cellular metabolism and survival. Leukemia stem cells (LSCs) are uniquely dependent on OXPHOS to support cellular metabolism and survival and are glycolytically deficient. LSCs rely on amino acid metabolism over fatty acid oxidation or glutamine to fuel the TCA cycle in most cases. In relapse LSCs however, fatty acid oxidation is upregulated under amino acid depletion and targeting multiple pathways is necessary.

Fig. 2.

Promising Drugs for targeting OXPHOS dependent AML cells and LSCs [,,–57,67,71,73,75,76]. Some AML cells and LSCs rely on OXPHOS to supply ATP for basic cellular functions and survival. This is a unique target for novel therapies such as ONC201, ONC212, IACS-010759 and ME-344. IACS-010759 and ME-344 suppress OXPHOS by directly targeting complexes of the ETC. While IACS-010759 has been shown to inhibit the activity of complex I, ME-344 can repress the contribution of both complex I and complex III to OXPHOS. On the other hand, ONC201 and ONC212 target the general functionality of mitochondria in AML cells through activation of the mitochondrial protease ClpP, ultimately leading to mitochondrial dysfunction and cell death.