Cotargeting of Mitochondrial Complex I and Bcl-2 Shows Antileukemic Activity against Acute Myeloid Leukemia Cells...

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Targeting oxidative phosphorylation (OXPHOS) is a key strategy for acute myeloid leukemia (AML) treatment.
• IACS-010759, a mitochondrial complex I inhibitor, shows preclinical anti-leukemic activity.
• Complex I inhibition can impede apoptosis by preventing cytochrome c release, a potential resistance mechanism.

Purpose of the Study:

• To investigate the synergistic antileukemic activity of combining IACS-010759 with a BH3 mimetic (venetoclax) in AML.
• To determine if this combination can overcome resistance mechanisms associated with complex I inhibition.
• To evaluate the efficacy of the combination in preclinical AML models.

Main Methods:

• Treatment of OXPHOS-reliant AML cell lines and primary patient samples with IACS-010759 and venetoclax.
• Assessment of apoptosis induction, cytochrome c release, and targeting of leukemia progenitor cells.
• Evaluation of the combination's efficacy in an AML xenograft mouse model.

Main Results:

• IACS-010759 and venetoclax synergistically induced apoptosis in AML cells and primary samples.
• The combination effectively targeted leukemia progenitor cells.
• In vivo studies showed prolonged survival in mice treated with the combination therapy.
• Venetoclax abolished IACS-010759-induced retention of cytochrome c, leading to apoptosis.

Conclusions:

• The combination of IACS-010759 and venetoclax demonstrates synergistic antileukemic activity in AML.
• This combination overcomes a key resistance mechanism by promoting cytochrome c release and apoptosis.
• Preclinical data support the further development of this combination for AML treatment.