Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia.

Abstract

Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a 'MitoScore' signature, which identifies high mitochondrial oxidative phosphorylation in vivo and in patients with AML. Primary AML cells with cytarabine (AraC) resistance and a high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) + AraC (but not to VEN + azacytidine). Single-cell transcriptomics of VEN + AraC-residual cell populations revealed adaptive resistance associated with changes in oxidative phosphorylation, electron transport chain complex and the TP53 pathway. Accordingly, treatment of VEN + AraC-resistant AML cells with electron transport chain complex inhibitors, pyruvate dehydrogenase inhibitors or mitochondrial ClpP protease agonists substantially delayed relapse following VEN + AraC. These findings highlight the central role of mitochondrial adaptation during AML therapy and provide a scientific rationale for alternating VEN + azacytidine with VEN + AraC in patients with a high MitoScore and to target mitochondrial metabolism to enhance the sensitivity of AML cells to currently approved therapies.

• Authors: Claudie Bosc, Estelle Saland, Aurélie Bousard, Noémie Gadaud, Marie Sabatier, Guillaume Cognet, Thomas Farge, Emeline Boet, Mathilde Gotanègre, Nesrine Aroua, Pierre-Luc Mouchel, Nathaniel Polley, Clément Larrue, Eléonore Kaphan, Muriel Picard, Ambrine Sahal, Latifa Jarrou, Marie Tosolini, Florian Rambow, Florence Cabon, Nathalie Nicot, Laura Poillet-Perez, Yujue Wang, Xiaoyang Su, Quentin Fovez, Jérôme Kluza, Rafael José Argüello, Céline Mazzotti, Hervé Avet-Loiseau, François Vergez, Jérôme Tamburini, Jean-Jacques Fournié, Ing S Tiong, Andrew H Wei, Tony Kaoma, Jean-Christophe Marine, Christian Récher, Lucille Stuani, Carine Joffre, Jean-Emmanuel Sarry
• Journal: Nature cancer (Nat Cancer) Vol. 2 Issue 11 Pg. 1204-1223 (11 2021) ISSN: 2662-1347 [Electronic] England
• PMID: 35122057 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Sulfonamides
• Cytarabine
• Azacitidine
• venetoclax

Topics

• Azacitidine (therapeutic use)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cytarabine (pharmacology)
• Humans
• Leukemia, Myeloid, Acute (drug therapy)
• Sulfonamides