Combinatory therapy targeting mitochondrial oxidative phosphorylation improves efficacy of IDH mutant inhibitors in acute myeloid leukemia

bioRxiv, August 2019

Lucille Stuani, Marie Sabatier, Feng Wang, Nathalie Poupin, Claudie Bosc, Estelle Saland, Florence Castelli, Lara Gales, Camille Montersino, Emeline Boet, Evgenia Turtoi, Tony Kaoma, Thomas Farge, Nicolas Broin, Clément Larrue, Natalia Baran, Marc Conti, Sylvain Loric, Pierre-Luc Mouchel, Mathilde Gotanègre, Cédric Cassan, Laurent Fernando, Guillaume Cognet, Aliki Zavoriti, Mohsen Hosseini, Héléna Boutzen, Kiyomi Morita, Andrew Futreal, Emeline Chu-Van, Laurent Le Cam, Martin Carroll, Mary A. Selak, Norbert Vey, Claire Calmettes, Arnaud Pigneux, Audrey Bidet, Rémy Castellano, Francois Fenaille, Andrei Turtoi, Guillaume Cazals, Pierre Bories, Yves Gibon, Brandon Nicolay, Sébastien Ronseaux, Joe Marszalek, Courtney D. DiNardo, Marina Konopleva, Yves Collette, Laetitia K. Linares, Floriant Bellvert, Fabien Jourdan, Koichi Takahashi, Christian Récher, Jean-Charles Portais, Jean-Emmanuel Sarry

Isocitrate dehydrogenases (IDH) are involved in redox control and central metabolism. Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, BCL-2 dependence and susceptibility to mitochondrial inhibitors in cancer cells. Here we show that high sensitivity to mitochondrial oxidative phosphorylation (OxPHOS) inhibitors is due to an enhanced mitochondrial oxidative metabolism in cell lines, PDX and patients with acute myeloid leukemia (AML) harboring IDH mutation. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurs through the increase in methylation-driven CEBP- and CPT1a-induced fatty acid oxidation, electron transport chain complex I activity and mitochondrial respiration in IDH1 mutant AML. Furthermore, an IDH mutant inhibitor that significantly and systematically reduces 2-HG oncometabolite transiently reverses mitochondrial FAO and OxPHOS gene signature and activities in patients who responded to the treatment and achieved the remission. However, at relapse or in patients who did not respond, IDH mutant inhibitor failed to block these mitochondrial properties. Accordingly, OxPHOS inhibitors such as IACS-010759 improve anti-AML efficacy of IDH mutant inhibitors alone and in combination with chemotherapy in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant-positive AML patients, especially those unresponsive to or relapsing from IDH mutant-specific inhibitors.