Abstract
Targeting oxidative phosphorylation (OXPHOS) is a promising strategy to improve treatment outcomes of acute myeloid leukemia (AML) patients. IACS-010759 is a mitochondrial complex I inhibitor that has demonstrated preclinical antileukemic activity and is being tested in Phase I clinical trials. However, complex I deficiency has been reported to inhibit apoptotic cell death through prevention of cytochrome c release. Thus, combining IACS-010759 with a BH3 mimetic may overcome this mechanism of resistance leading to synergistic antileukemic activity against AML. In this study, we show that IACS-010759 and venetoclax synergistically induce apoptosis in OXPHOS-reliant AML cell lines and primary patient samples and cooperatively target leukemia progenitor cells. In a relatively OXPHOS-reliant AML cell line derived xenograft mouse model, IACS-010759 treatment significantly prolonged survival, which was further enhanced by treatment with IACS-010759 in combination with venetoclax. Consistent with our hypothesis, IACS-010759 treatment indeed retained cytochrome c in mitochondria, which was completely abolished by venetoclax, resulting in Bak/Bax- and caspase-dependent apoptosis. Our preclinical data provide a rationale for further development of the combination of IACS-010759 and venetoclax for the treatment of patients with AML.
Highlights
While overall survival rates of patients with acute myeloid leukemia (AML) have improved over the past several decades, improvement has been incremental [1]
To test our hypothesis that IACS-010759 synergizes with venetoclax in inducing apoptosis in AML cells, we tested variable concentrations of IACS-010759 and venetoclax, alone and in combination, in AML cell lines
IACS-010759 synergizes with venetoclax in inducing apoptosis oxidativephosphorylation phosphorylation
Summary
While overall survival rates of patients with acute myeloid leukemia (AML) have improved over the past several decades, improvement has been incremental [1]. The majority of AML patients treated with standard induction chemotherapy initially respond, there is a high rate of relapse due to the survival of some leukemia initiating/stem cells [2,3]. IACS-010759 is a selective small-molecule inhibitor of mitochondrial complex I that shows antileukemic activity in vitro as well as in AML xenograft models [8]. It is currently being investigated in Phase I clinical trials to determine tolerability, safety, and pharmacokinetics in patients with AML, relapsed refractory lymphoma, or advanced, metastatic, or unresectable solid tumors (www.clinicaltrials.gov). It is conceivable that inhibition of complex I with IACS-010759 may block cytochrome c release, resulting in limited apoptosis in AML cells, representing a mechanism of resistance to this promising mitochondria-targeting agent
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