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

doi:10.1016/j.ccell.2019.06.003

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

doi: 10.1016/j.ccell.2019.06.003.

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

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

Affiliations

¹ 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.
² 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; Department of Chemistry, Université de Montréal Pavillon Roger-Gaudry, 2900 Boulevard Édouard-Montpetit, Montréal, QC H3C 3J7, Canada.
³ 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.
⁴ 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; Department of Pathology & Cell Biology, Université de Montréal, 2900 Boulevard Édouard-Montpetit, Montréal QC H3T 1J4, Canada.
⁵ 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; Department of Computer Science & Operations Research, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada; Department of Biochemistry & Molecular Medicine, Université de Montréal Pavillon Roger-Gaudry, 2900 Boulevard Édouard-Montpetit, Montréal, QC H3T 1J4, Canada.
⁶ 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; Leukemia Cell Bank of Quebec, 5415 Assumption Boulevard, Montréal, QC H1T 2M4, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, 5415 Assumption Boulevard, Montréal, QC H1T 2M4, Canada; Department of Medicine, Université de Montréal, 2900 Boulevard Édouard-Montpetit, Montréal, QC H3T 1J4, Canada.
⁷ 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; Department of Chemistry, Université de Montréal Pavillon Roger-Gaudry, 2900 Boulevard Édouard-Montpetit, Montréal, QC H3C 3J7, Canada. Electronic address: anne.marinier@iric.chimie.ca.
⁸ 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; Leukemia Cell Bank of Quebec, 5415 Assumption Boulevard, Montréal, QC H1T 2M4, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, 5415 Assumption Boulevard, Montréal, QC H1T 2M4, Canada; Department of Medicine, Université de Montréal, 2900 Boulevard Édouard-Montpetit, Montréal, QC H3T 1J4, Canada. Electronic address: guy.sauvageau@umontreal.ca.

PMID: 31287994
DOI: 10.1016/j.ccell.2019.06.003

Free article

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

Irène Baccelli et al. Cancer Cell. 2019.

Free article

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

doi: 10.1016/j.ccell.2019.06.003.

Authors

Affiliations

¹ 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.
² 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; Department of Chemistry, Université de Montréal Pavillon Roger-Gaudry, 2900 Boulevard Édouard-Montpetit, Montréal, QC H3C 3J7, Canada.
³ 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.
⁴ 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; Department of Pathology & Cell Biology, Université de Montréal, 2900 Boulevard Édouard-Montpetit, Montréal QC H3T 1J4, Canada.
⁵ 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; Department of Computer Science & Operations Research, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada; Department of Biochemistry & Molecular Medicine, Université de Montréal Pavillon Roger-Gaudry, 2900 Boulevard Édouard-Montpetit, Montréal, QC H3T 1J4, Canada.
⁶ 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; Leukemia Cell Bank of Quebec, 5415 Assumption Boulevard, Montréal, QC H1T 2M4, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, 5415 Assumption Boulevard, Montréal, QC H1T 2M4, Canada; Department of Medicine, Université de Montréal, 2900 Boulevard Édouard-Montpetit, Montréal, QC H3T 1J4, Canada.
⁷ 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; Department of Chemistry, Université de Montréal Pavillon Roger-Gaudry, 2900 Boulevard Édouard-Montpetit, Montréal, QC H3C 3J7, Canada. Electronic address: anne.marinier@iric.chimie.ca.
⁸ 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; Leukemia Cell Bank of Quebec, 5415 Assumption Boulevard, Montréal, QC H1T 2M4, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, 5415 Assumption Boulevard, Montréal, QC H1T 2M4, Canada; Department of Medicine, Université de Montréal, 2900 Boulevard Édouard-Montpetit, Montréal, QC H3T 1J4, Canada. Electronic address: guy.sauvageau@umontreal.ca.

PMID: 31287994
DOI: 10.1016/j.ccell.2019.06.003

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.

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

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

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