RAS activation induces synthetic lethality of MEK inhibition with mitochondrial oxidative metabolism in acute myeloid leukemia

Article Article scientifique Article RAS activation induces synthetic lethality of MEK inhibition with mitochondrial oxidative metabolism in acute myeloid leukemia eng 2022-03-30 2022-05 author Decroocq Justine 0000-0002-9924-2979 Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France.,Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France. author Birsen Rudy 0000-0001-9696-870X Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France.,Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France. author Montersino Camille Centre de Recherche en Cancérologie de Marseille (Cancer Research Center of Marseille.), CRCM, Inserm UMR1068, CNRS UMR7258, Aix Marseille Université U105, Institut Paoli Calmettes, Marseille, France. author Chaskar Prasad Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Center Leman, Geneva, Switzerland. 913442 author Mano Jordi 0000-0002-6665-6390 Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France.,Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France. author Poulain Laury Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Center Leman, Geneva, Switzerland. 916197 author Friedrich Chloe Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France.,Hematology Laboratory, Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris, Cochin Hospital, Paris, France. author Alary Anne-Sophie Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France.,Hematology Laboratory, Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris, Cochin Hospital, Paris, France. author Guermouche Helene 0000-0003-4074-1623 Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France.,Hematology Laboratory, Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris, Cochin Hospital, Paris, France. author Sahal Ambrine Cancer Research Center of Toulouse, Unité Mixtes de Recherche 1037 INSERM, Toulouse, France. author Fouquet Guillemette 0000-0002-3751-393X Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France. author Gotanègre Mathilde Cancer Research Center of Toulouse, Unité Mixtes de Recherche 1037 INSERM, Toulouse, France. author Simonetta Federico 0000-0002-0399-689X Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Center Leman, Geneva, Switzerland. 936876 Département de médecine (DEMED) author Mouche Sarah 0000-0002-2348-1746 Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Center Leman, Geneva, Switzerland. 103490 Département de médecine (DEMED) author Gestraud Pierre 0000-0002-3893-9879 Bioinformatics Platform- U900, Institut Curie, PSL Research University, Paris, France. author Lescure Auriane BioPhenics High-Content Screening Laboratory, Cell and Tissue Imaging Facility (PICT-IBiSA), Institut Curie, PSL Research University, Translational Research Department, Paris, France. author Del Nery Elaine 0000-0002-9654-5202 BioPhenics High-Content Screening Laboratory, Cell and Tissue Imaging Facility (PICT-IBiSA), Institut Curie, PSL Research University, Translational Research Department, Paris, France. author Bosc Claudie 0000-0003-1435-3475 Cancer Research Center of Toulouse, Unité Mixtes de Recherche 1037 INSERM, Toulouse, France. author Grenier Adrien Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France.,Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France. author Mazed Fetta Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France.,Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France. author Mondesir Johanna 0000-0001-9449-5195 Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France.,Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France. author Chapuis Nicolas 0000-0003-0601-3948 Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France.,Hematology Laboratory, Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris, Cochin Hospital, Paris, France. author Ho-Mohrle Liza Kwok-Fung Pathology department, Geneva University Hospital, 1211, Geneva 4, Switzerland. 133434 author Boughalem Aicha Cytogenetic Laboratory, Necker Hospital, Paris, France. author Lelorc'h Marc Cytogenetic Laboratory, Necker Hospital, Paris, France. author Gobeaux Camille Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France. author Fontenay Michaela Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France.,Hematology Laboratory, Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris, Cochin Hospital, Paris, France. author Recher Christian Hematology Laboratory, Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris, Cochin Hospital, Paris, France. author Vey Norbert 0000-0001-7027-040X Hematology Department, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France. author Guillé Arnaud Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Predictive Oncology, Aix-Marseille Université, Marseille, France. author Birnbaum Daniel 0000-0001-7920-9883 Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Predictive Oncology, Aix-Marseille Université, Marseille, France. author Hermine Olivier Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France.,Service d'Hématologie Adultes, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France.,Institut Imagine, INSERM U1163, 75015, Paris, France. author Radford-Weiss Isabelle Cytogenetic Laboratory, Necker Hospital, Paris, France. author Tsantoulis Petros 0000-0003-3613-6682 Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Center Leman, Geneva, Switzerland. 861166 Département de médecine (DEMED) author Collette Yves 0000-0001-5359-7099 Centre de Recherche en Cancérologie de Marseille (Cancer Research Center of Marseille.), CRCM, Inserm UMR1068, CNRS UMR7258, Aix Marseille Université U105, Institut Paoli Calmettes, Marseille, France. author Castellano Rémy Centre de Recherche en Cancérologie de Marseille (Cancer Research Center of Marseille.), CRCM, Inserm UMR1068, CNRS UMR7258, Aix Marseille Université U105, Institut Paoli Calmettes, Marseille, France. author Sarry Jean-Emmanuel 0000-0002-6704-2032 Hematology Laboratory, Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris, Cochin Hospital, Paris, France. author Pasmant Eric 0000-0002-1881-8762 Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France. author Bouscary Didier Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France.,Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France. author Kosmider Olivier Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France.,Hematology Laboratory, Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris, Cochin Hospital, Paris, France. author Tamburini Bonnefoy Jérôme 0000-0002-0167-5996 Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, F-75014, Paris, France. jerome.tamburinibonnefoy@unige.ch.,Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France. jerome.tamburinibonnefoy@unige.ch.,Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Center Leman, Geneva, Switzerland. jerome.tamburinibonnefoy@unige.ch. 909914 Département de médecine (DEMED) 1237-1252 10.1038/s41375-022-01541-0 35354920 0887-6924 PMC9061298 https://www.nature.com/articles/s41375-022-01541-0 Despite recent advances in acute myeloid leukemia (AML) molecular characterization and targeted therapies, a majority of AML cases still lack therapeutically actionable targets. In 127 AML cases with unmet therapeutic needs, as defined by the exclusion of ELN favorable cases and of FLT3-ITD mutations, we identified 51 (40%) cases with alterations in RAS pathway genes (RAS+, mostly NF1, NRAS, KRAS, and PTPN11 genes). In 79 homogeneously treated AML patients from this cohort, RAS+ status were associated with higher white blood cell count, higher LDH, and reduced survival. In AML models of oncogenic addiction to RAS-MEK signaling, the MEK inhibitor trametinib demonstrated antileukemic activity in vitro and in vivo. However, the efficacy of trametinib was heterogeneous in ex vivo cultures of primary RAS+ AML patient specimens. From repurposing drug screens in RAS-activated AML cells, we identified pyrvinium pamoate, an anti-helminthic agent efficiently inhibiting the growth of RAS+ primary AML cells ex vivo, preferentially in trametinib-resistant PTPN11- or KRAS-mutated samples. Metabolic and genetic complementarity between trametinib and pyrvinium pamoate translated into anti-AML synergy in vitro. Moreover, this combination inhibited the propagation of RA+ AML cells in vivo in mice, indicating a potential for future clinical development of this strategy in AML. Animals Humans Leukemia, Myeloid, Acute / drug therapy Leukemia, Myeloid, Acute / genetics Leukemia, Myeloid, Acute / metabolism Mice Mitogen-Activated Protein Kinase Kinases / genetics Mutation Oxidative Stress Proto-Oncogene Proteins p21(ras) / genetics Proto-Oncogene Proteins p21(ras) / metabolism Synthetic Lethal Mutations Fms-Like Tyrosine Kinase 3 / metabolism Dewey 616 Dewey 616.07 56 Département de médecine 221 137 Département de pathologie et immunologie 21F false 1216 Leucémie et transplantation allogénique de cellules souches hématopoïétiques 982 1257 Lymphomes et leucémies 994 Leukemia 36 5 e5971be2-6bb5-4639-b1f3-a29aba8cd24f Article (Published version) Public Article_scientifique_from_unpaywall.pdf 4980645 application/pdf CC BY-4.0 76418cc08131a7c9575fe08331523727bd0623eba556921e7ba30bbce0d6667d 7928b0ad-2dd4-4928-a0e2-b09b7c65c954 Supplemental data Public 41375_2022_1541_MOESM1_ESM.pdf 2587312 application/pdf ad1a8f439d06dc23cae3a0a44bfbefc7a1872b59377a363d055852cc33e9847f openAccess Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

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