| Literature DB >> 31287994 |
Irène Baccelli1, Yves Gareau2, Bernhard Lehnertz3, Stéphane Gingras2, Jean-François Spinella3, Sophie Corneau3, Nadine Mayotte3, Simon Girard3, Mélanie Frechette3, Valérie Blouin-Chagnon3, Koryne Leveillé3, Isabel Boivin3, Tara MacRae3, Jana Krosl3, Clarisse Thiollier3, Vincent-Philippe Lavallée3, Evgeny Kanshin3, Thierry Bertomeu3, Jasmin Coulombe-Huntington3, Corinne St-Denis3, Marie-Eve Bordeleau3, Geneviève Boucher3, Philippe P Roux4, Sébastien Lemieux5, Mike Tyers3, Pierre Thibault3, Josée Hébert6, Anne Marinier7, Guy Sauvageau8.
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.Entities:
Keywords: NADH dehydrogenase inhibitor; acute myeloid leukemia; electron transport chain complex I; metabolism; mitochondrial respiration; oxidative phosphorylation; personalized medicine; therapeutic target
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Year: 2019 PMID： 31287994 DOI： 10.1016/j.ccell.2019.06.003
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743