title: The NAE inhibitor pevonedistat interacts with the HDAC inhibitor belinostat to target AML cells by disrupting the DDR.
abstract: Two classes of novel agents, NEDD8-activating enzyme (NAE) and histone deacetylase (HDAC) inhibitors, have shown single-agent activity in acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS). Here we examined mechanisms underlying interactions between the NAE inhibitor pevonedistat (MLN4924) and the approved HDAC inhibitor belinostat in AML/MDS cells. MLN4924/belinostat coadministration synergistically induced AML cell apoptosis with or without p53 deficiency or FLT3-internal tandem duplication (ITD), whereas p53 short hairpin RNA (shRNA) knockdown or enforced FLT3-ITD expression significantly sensitized cells to the regimen. MLN4924 blocked belinostat-induced antiapoptotic gene expression through nuclear factor-κB inactivation. Each agent upregulated Bim, and Bim knockdown significantly attenuated apoptosis. Microarrays revealed distinct DNA damage response (DDR) genetic profiles between individual vs combined MLN4924/belinostat exposure. Whereas belinostat abrogated the MLN4924-activated intra-S checkpoint through Chk1 and Wee1 inhibition/downregulation, cotreatment downregulated multiple homologous recombination and nonhomologous end-joining repair proteins, triggering robust double-stranded breaks, chromatin pulverization, and apoptosis. Consistently, Chk1 or Wee1 shRNA knockdown significantly sensitized AML cells to MLN4924. MLN4924/belinostat displayed activity against primary AML or MDS cells, including those carrying next-generation sequencing-defined poor-prognostic cancer hotspot mutations, and CD34(+)/CD38(-)/CD123(+) populations, but not normal CD34(+) progenitors. Finally, combined treatment markedly reduced tumor burden and significantly prolonged animal survival (P < .0001) in AML xenograft models with negligible toxicity, accompanied by pharmacodynamic effects observed in vitro. Collectively, these findings argue that MLN4924 and belinostat interact synergistically by reciprocally disabling the DDR in AML/MDS cells. This strategy warrants further consideration in AML/MDS, particularly in disease with unfavorable genetic aberrations.
authors: Division of Hematology and Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA;
authors: Liang
authors: L
authors: Zhou
authors: Division of Hematology and Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA;
authors: Shuang
authors: S
authors: Chen
authors: Division of Hematology and Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA;
authors: Yu
authors: Y
authors: Zhang
authors: Division of Hematology and Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA;
authors: Maciej
authors: M
authors: Kmieciak
authors: Division of Hematology and Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA; Department of Hematology, Beijing Chaoyang Hospital of Capital Medical University, Beijing, China;
authors: Yun
authors: Y
authors: Leng
authors: Division of Hematology and Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA; Department of Hematology, Beijing Chaoyang Hospital of Capital Medical University, Beijing, China;
authors: Lihong
authors: L
authors: Li
authors: Division of Hematology and Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA;
authors: Hui
authors: H
authors: Lin
authors: Division of Molecular Diagnostics, Department of Pathology and.
authors: Kathryn A
authors: KA
authors: Rizzo
authors: Division of Molecular Diagnostics, Department of Pathology and.
authors: Catherine I
authors: CI
authors: Dumur
authors: Division of Molecular Diagnostics, Department of Pathology and.
authors: Andrea
authors: A
authors: Ferreira-Gonzalez
authors: Division of Hematology and Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA;
authors: Mohamed
authors: M
authors: Rahmani
authors: Department of Pharmacology, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA;
authors: Lawrence
authors: L
authors: Povirk
authors: Department of Pharmacology, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA;
authors: Sri
authors: S
authors: Chalasani
authors: Oncology Drug Discovery Unit, Millennium Pharmaceuticals, Inc/Takeda Pharmaceutical Company Ltd, Cambridge, MA;
authors: Allison J
authors: AJ
authors: Berger
authors: Division of Hematology and Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA; Cancer Center, The First Hospital, Jilin University, Changchun, Jilin, China; and.
authors: Yun
authors: 0000-0003-2285-0818
authors: Y
authors: Dai
authors: Division of Hematology and Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA; Department of Biochemistry, Virginia Commonwealth University and the Massey Cancer Center and the Virginia Institute of Molecular Medicine, Richmond, VA.
authors: Steven
authors: 0000-0003-4452-9320
authors: S
authors: Grant
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000072224:Bcl-2-Like Protein 11 / Q000037:antagonists & inhibitors / Q000235:genetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D002478:Cells, Cultured; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics; D003517:Cyclopentanes / Q000494:pharmacology / Q000627:therapeutic use*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D058990:Molecular Targeted Therapy; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D020298:U937 Cells; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000072224:Bcl-2-Like Protein 11; D018797:Cell Cycle Proteins; D003517:Cyclopentanes; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011743:Pyrimidines; D034741:RNA, Small Interfering; D013449:Sulfonamides; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human; C487081:belinostat; C539933:pevonedistat