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

Publication date: 8 July 2019Source: Cancer Cell, Volume 36, Issue 1Author(s): 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-DenisSummaryTo 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.
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research