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

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

Irène Baccelli, Yves Gareau, Bernhard Lehnertz, Stéphane Gingras, Jean-François Spinella, Sophie Corneau, Nadine Mayotte, Simon Girard, Mélanie Frechette, Valérie Blouin-Chagnon, Koryne Leveillé, Isabel Boivin, etc.

Cancer Cell. 2019 Jul 8;36(1):84-99.e8.

PMID: 31287994

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP366017096	Mubritinib		366017-09-6	Price

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