Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of OXPHOS Dependency in Acute Myeloid Leukemia

Cancer Cell. 2019 Jul 8;36(1):84-99.e8. doi: 10.1016/j.ccell.2019.06.003.

Abstract

To identify therapeutic targets in acute myeloid leukemia (AML), we chemically interrogated 200 sequenced primary specimens. Mubritinib, a known ERBB2 inhibitor, elicited strong anti-leukemic effects in vitro and in vivo. In the context of AML, mubritinib functions through ubiquinone-dependent inhibition of electron transport chain (ETC) complex I activity. Resistance to mubritinib characterized normal CD34+ hematopoietic cells and chemotherapy-sensitive AMLs, which displayed transcriptomic hallmarks of hypoxia. Conversely, sensitivity correlated with mitochondrial function-related gene expression levels and characterized a large subset of chemotherapy-resistant AMLs with oxidative phosphorylation (OXPHOS) hyperactivity. Altogether, our work thus identifies an ETC complex I inhibitor and reveals the genetic landscape of OXPHOS dependency in AML.

Keywords: NADH dehydrogenase inhibitor; acute myeloid leukemia; electron transport chain complex I; metabolism; mitochondrial respiration; oxidative phosphorylation; personalized medicine; therapeutic target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Biomarkers
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Electron Transport Complex I / antagonists & inhibitors*
  • Female
  • Hematopoiesis / drug effects
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / mortality
  • Mice
  • Models, Biological
  • Oxazoles / pharmacology*
  • Oxidative Phosphorylation / drug effects*
  • Protein Kinase Inhibitors / pharmacology*
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Triazoles / pharmacology*

Substances

  • Antineoplastic Agents
  • Biomarkers
  • Oxazoles
  • Protein Kinase Inhibitors
  • TAK-165
  • Triazoles
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Electron Transport Complex I