Re-evaluating the rationale for targeting oxidative phosphorylation in acute myeloid leukemia.

Area of Science:

• Mitochondrial biology
• Cancer metabolism
• Pharmacology

Background:

• Targeting mitochondrial oxidative phosphorylation (OxPhos) is a cancer therapy strategy, especially for acute myeloid leukemia (AML).
• Early research suggested leukemic cells disproportionately rely on OxPhos, implying a therapeutic window for electron transport system (ETS) inhibition.
• However, clinical outcomes of broad OxPhos inhibition have been disappointing.

Purpose of the Study:

• To critically evaluate the role of OxPhos in cancer, particularly AML.
• To differentiate essential mitochondrial processes from those that are merely compensatory or artifactual.
• To establish criteria for identifying targetable mitochondrial liabilities with a realistic therapeutic index.

Main Methods:

• Review of existing literature on OxPhos in cancer and normal tissues.
• Analysis of common assays used to infer OxPhos dependency (e.g., oxygen consumption rate, transcriptomic signatures).
• Case study using the Complex I inhibitor IACS-010759 to illustrate challenges of systemic ETS inhibition.

Main Results:

• OxPhos capacity and flux vary significantly across normal tissues and cancers; highly oxidative organs often have higher respiratory flux than tumors.
• Oxygen consumption rate (OCR) and transcriptomic signatures are often incomplete or misleading indicators of OxPhos dependency.
• Systemic ETS inhibition can lead to dose-limiting toxicities due to essential roles of OxPhos in normal tissues.

Conclusions:

• The critical question is not whether mitochondria matter for cancer, but whether specific mitochondrial processes are disproportionately essential to malignant cells compared to vital organs.
• Assays for OxPhos dependency in AML require careful interpretation, accounting for mitochondrial content and potential artifacts like ATP synthase reversal.
• Developing effective cancer therapies targeting mitochondria requires precise identification of liabilities with a favorable therapeutic index, rather than broad inhibition.