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

View ORCID ProfileLucille 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, View ORCID ProfileJean-Emmanuel Sarry
doi: https://doi.org/10.1101/749580
Lucille Stuani
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, France
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  • ORCID record for Lucille Stuani
Marie Sabatier
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, France
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Feng Wang
Departments of Leukemia and Genomic Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
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Nathalie Poupin
UMR1331 Toxalim, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
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Claudie Bosc
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, France
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Estelle Saland
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, France
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Florence Castelli
CEA/DSV/iBiTec-S/SPI, Laboratoire d’Etude du Métabolisme des Médicaments, MetaboHUB-Paris, F-91191 Gif-sur-Yvette, France
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Lara Gales
TBI, Université de Toulouse, CNRS, INRA, INSA, Toulouse, F-31077, FranceMetaToul-MetaboHUB, National Infrastructure of Metabolomics and Fluxomics, Toulouse, F-31077, France
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Camille Montersino
Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Marseille, France
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Emeline Boet
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, France
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Evgenia Turtoi
Inserm, U1194, Cancer Research Institute of Montpellier, Tumor Microenvironment Lab, F-34090 Montpellier, FranceInstitut du Cancer de Montpellier, F-34090 Montpellier, FranceUniversité de Montpellier, F-34090 Montpellier, France
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Tony Kaoma
Proteome and Genome Research Unit, Department of Oncology, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg
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Thomas Farge
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, France
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Nicolas Broin
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, France
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Clément Larrue
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, France
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Natalia Baran
Departments of Leukemia and Genomic Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
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Marc Conti
Inserm U955EQ7, IMRB, Créteil, France
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Sylvain Loric
Inserm U955EQ7, IMRB, Créteil, France
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Pierre-Luc Mouchel
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, FranceService d’Hématologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse, F-31100 Toulouse, France
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Mathilde Gotanègre
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, France
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Cédric Cassan
UMR1332 Biologie du Fruit et Pathologie, Plateforme Métabolome Bordeaux, INRA, Université de Bordeaux, F-33883 Villenave d’Ornon, France
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Laurent Fernando
UMR1331 Toxalim, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
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Guillaume Cognet
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, France
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Aliki Zavoriti
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, France
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Mohsen Hosseini
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, France
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Héléna Boutzen
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, France
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Kiyomi Morita
Departments of Leukemia and Genomic Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
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Andrew Futreal
Departments of Leukemia and Genomic Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
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Emeline Chu-Van
CEA/DSV/iBiTec-S/SPI, Laboratoire d’Etude du Métabolisme des Médicaments, MetaboHUB-Paris, F-91191 Gif-sur-Yvette, France
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Laurent Le Cam
Institut du Cancer de Montpellier, F-34090 Montpellier, FranceUniversité de Montpellier, F-34090 Montpellier, France
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Martin Carroll
Division of Hematology & Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Mary A. Selak
Division of Hematology & Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Norbert Vey
Institut Paoli-Calmettes and Aix-Marseille Université, Marseille, France
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Claire Calmettes
CHU Bordeaux, Service d’Hématologie Clinique, F-33000 Bordeaux, France
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Arnaud Pigneux
CHU Bordeaux, Service d’Hématologie Clinique, F-33000 Bordeaux, France
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Audrey Bidet
CHU Bordeaux, Service d’Hématologie Biologique, F-33000 Bordeaux, France
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Rémy Castellano
Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Marseille, France
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Francois Fenaille
CEA/DSV/iBiTec-S/SPI, Laboratoire d’Etude du Métabolisme des Médicaments, MetaboHUB-Paris, F-91191 Gif-sur-Yvette, France
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Andrei Turtoi
Inserm, U1194, Cancer Research Institute of Montpellier, Tumor Microenvironment Lab, F-34090 Montpellier, FranceInstitut du Cancer de Montpellier, F-34090 Montpellier, FranceUniversité de Montpellier, F-34090 Montpellier, France
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Guillaume Cazals
Laboratoire de Mesures Physiques, Université de Montpellier, F-34090 Montpellier, France
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Pierre Bories
Réseau régional de Cancérologie Onco-Occitanie, Toulouse, France
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Yves Gibon
UMR1332 Biologie du Fruit et Pathologie, Plateforme Métabolome Bordeaux, INRA, Université de Bordeaux, F-33883 Villenave d’Ornon, France
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Brandon Nicolay
Agios Pharmaceuticals, 88 Sydney St, Cambridge MA, USA
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Sébastien Ronseaux
Agios Pharmaceuticals, 88 Sydney St, Cambridge MA, USA
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Joe Marszalek
Departments of Leukemia and Genomic Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
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Courtney D. DiNardo
Departments of Leukemia and Genomic Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
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Marina Konopleva
Departments of Leukemia and Genomic Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
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Yves Collette
Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Marseille, France
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Laetitia K. Linares
Institut du Cancer de Montpellier, F-34090 Montpellier, FranceUniversité de Montpellier, F-34090 Montpellier, France
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Floriant Bellvert
TBI, Université de Toulouse, CNRS, INRA, INSA, Toulouse, F-31077, FranceMetaToul-MetaboHUB, National Infrastructure of Metabolomics and Fluxomics, Toulouse, F-31077, France
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Fabien Jourdan
UMR1331 Toxalim, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, FranceMetaToul-MetaboHUB, National Infrastructure of Metabolomics and Fluxomics, Toulouse, F-31077, France
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Koichi Takahashi
Departments of Leukemia and Genomic Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
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Christian Récher
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, FranceService d’Hématologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse, F-31100 Toulouse, France
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Jean-Charles Portais
TBI, Université de Toulouse, CNRS, INRA, INSA, Toulouse, F-31077, FranceMetaToul-MetaboHUB, National Infrastructure of Metabolomics and Fluxomics, Toulouse, F-31077, France
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Jean-Emmanuel Sarry
Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, France
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  • ORCID record for Jean-Emmanuel Sarry
  • For correspondence: jean-emmanuel.sarry@inserm.fr
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Abstract

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 CEBPα- 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.

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Combinatory therapy targeting mitochondrial oxidative phosphorylation improves efficacy of IDH mutant inhibitors in acute myeloid leukemia
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
bioRxiv 749580; doi: https://doi.org/10.1101/749580
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Combinatory therapy targeting mitochondrial oxidative phosphorylation improves efficacy of IDH mutant inhibitors in acute myeloid leukemia
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
bioRxiv 749580; doi: https://doi.org/10.1101/749580

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