title: Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction inIDH2- andTET2-Mutant Acute Myeloid Leukemia.
abstract: Genomic studies in acute myeloid leukemias (AML) have identified mutations that drive altered DNA methylation, includingTET2andIDH2Here, we show that models of AML resulting fromTET2orIDH2mutations combined withFLT3ITDmutations are sensitive to 5-azacytidine or to the IDH2 inhibitor AG-221, respectively. 5-azacytidine and AG-221 treatment induced an attenuation of aberrant DNA methylation and transcriptional output and resulted in a reduction in leukemic blasts consistent with antileukemic activity. These therapeutic benefits were associated with restoration of leukemic cell differentiation, and the normalization of hematopoiesis was derived from mutant cells. By contrast, combining AG-221 or 5-azacytidine with FLT3 inhibition resulted in a reduction in mutant allele burden, progressive recovery of normal hematopoiesis from non-mutant stem-progenitor cells, and reversal of dysregulated DNA methylation and transcriptional output. Together, our studies suggest combined targeting of signaling and epigenetic pathways can increase therapeutic response in AML.Significance:AMLs with mutations inTET2orIDH2are sensitive to epigenetic therapy through inhibition of DNA methyltransferase activity by 5-azacytidine or inhibition of mutant IDH2 through AG-221. These inhibitors induce a differentiation response and can be used to inform mechanism-based combination therapy.Cancer Discov; 7(5); 494-505. ©2017 AACR.See related commentary by Thomas and Majeti, p. 459See related article by Yen et al., p. 478This article is highlighted in the In This Issue feature, p. 443.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Shih
authors.affiliation: Department of Medicine/Hematology-Oncology and Department of Pharmacology, Weill Cornell Medical College, New York, New York.|Department of Physiology and Biophysics and the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Cem
authors.initials: C
authors.lastname: Meydan
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Shank
authors.affiliation: Department of Medicine/Hematology-Oncology and Department of Pharmacology, Weill Cornell Medical College, New York, New York.
authors.forename: Francine E
authors.initials: FE
authors.lastname: Garrett-Bakelman
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Ward
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Intlekofer
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Abbas
authors.initials: A
authors.lastname: Nazir
authors.affiliation: Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Eytan M
authors.initials: EM
authors.lastname: Stein
authors.affiliation: Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kristina
authors.initials: K
authors.lastname: Knapp
authors.affiliation: Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Medicine/Hematology-Oncology and Department of Pharmacology, Weill Cornell Medical College, New York, New York.
authors.forename: Jacob
authors.initials: J
authors.lastname: Glass
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Travins
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Kim
authors.initials: K
authors.lastname: Straley
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Camelia
authors.initials: C
authors.lastname: Gliser
authors.affiliation: Department of Physiology and Biophysics and the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Mason
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Katharine
authors.initials: K
authors.lastname: Yen
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.affiliation: Department of Medicine/Hematology-Oncology and Department of Pharmacology, Weill Cornell Medical College, New York, New York. leviner@mskcc.org amm2014@med.cornell.edu.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. leviner@mskcc.org amm2014@med.cornell.edu.|Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.|Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001374:Azacitidine / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D044127:Epigenesis, Genetic / Q000187:drug effects; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D058990:Molecular Targeted Therapy / Q000379:methods*; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D014227:Triazines / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D000631:Aminopyridines; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D014227:Triazines; C000605269:enasidenib; D007521:Isocitrate Dehydrogenase; C000599591:isocitrate dehydrogenase 2, mouse; D049308:Dioxygenases; C551914:Tet2 protein, mouse; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3; D001374:Azacitidine