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, Tara Macrae, Jana Krosl, Clarisse Thiollier, Vincent-Philippe Lavallée, Evgeny Kanshin, Thierry Bertomeu, Jasmin Coulombe-Huntington, Corinne St-Denis, Marie-Eve Bordeleau, Geneviève Boucher, P. Philippe Roux, Sébastien Lemieux, Mike Tyers, Pierre Thibault, Josée Hébert, Anne Marinier, Guy Sauvageau

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.,

Type

Journal article

Publication

Cancer Cell

Sébastien Lemieux

Principal Investigator

Principal Investigator, Functional and Structural Bioinformatics Research Unit, IRIC | Scientific direction of the Bioinformatics platform | Associate Professor, Department of Biochemistry and Molecular Medicine, Université de Montréal