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

Publication — IRIC

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.

Publication date: July 8, 2019
Principal Investigators: Baccelli I, Gareau Y, Lehnertz B, Gingras S, Spinella JF, Corneau S, Mayotte N, Girard S, Frechette M, Blouin-Chagnon V, Leveillé K, Boivin I, MacRae T, Krosl J, Thiollier C, Lavallée VP, Kanshin E, Bertomeu T, Coulombe-Huntington J, St-Denis C, Bordeleau ME, Boucher G, Roux PP, Lemieux S, Tyers M, Thibault P, Hébert J, Marinier A, Sauvageau G
PubMed reference: Cancer Cell 2019;36(1):84-99.e8
PubMed ID: 31287994
Affiliation: The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada. Electronic address: baccelli@gmail.com.