title: Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo.
abstract: MK-1775 is the first-in-class selective Wee1 inhibitor which has been demonstrated to synergize with CHK1 inhibitors in various malignancies. In this study, we report that the pan-histone deacetylase inhibitor (HDACI) panobinostat synergizes with MK-1775 in acute myeloid leukemia (AML), a malignancy which remains a clinical challenge and requires more effective therapies. Using both AML cell line models and primary patient samples, we demonstrated that panobinostat and MK-1775 synergistically induced proliferation arrest and cell death. We also demonstrated that panobinostat had equal anti-leukemic activities against primary AML blasts derived from patients either at initial diagnosis or at relapse. Interestingly, treatment with panobinostat alone or in combination with MK-1775 resulted in decreased Wee1 protein levels as well as downregulation of the CHK1 pathway. shRNA knockdown of CHK1 significantly sensitized AML cells to MK-1775 treatment, while knockdown of Wee1 significantly enhanced both MK-1775- and panobinostat-induced cell death. Our results demonstrate that panobinostat synergizes with MK-1775 in AML cells, at least in part through downregulation of CHK1 and/or Wee1, providing compelling evidence for the clinical development of the combination treatment in AML.
authors.affiliation: a National Engineering Laboratory for AIDS Vaccine; Key Laboratory for Molecular Enzymology and Engineering; the Ministry of Education; School of Life Sciences; Jilin University ; Changchun , China.
authors.forename: Wenxiu
authors.initials: W
authors.lastname: Qi
authors.affiliation: a National Engineering Laboratory for AIDS Vaccine; Key Laboratory for Molecular Enzymology and Engineering; the Ministry of Education; School of Life Sciences; Jilin University ; Changchun , China.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhang
authors.affiliation: b Department of Oncology ; Wayne State University School of Medicine ; Detroit , MI USA.|c Molecular Therapeutics Program; Barbara Ann Karmanos Cancer Institute; Wayne State University School of Medicine ; Detroit , MI USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Edwards
authors.affiliation: d Department of Pediatrics ; Wayne State University School of Medicine ; Detroit , MI USA.|e Division of Pediatric Hematology/Oncology; Children's Hospital of Michigan ; Detroit , MI USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Chu
authors.affiliation: h Department of Biological Sciences; Oakland University ; Rochester , MI USA.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Madlambayan
authors.affiliation: c Molecular Therapeutics Program; Barbara Ann Karmanos Cancer Institute; Wayne State University School of Medicine ; Detroit , MI USA.|d Department of Pediatrics ; Wayne State University School of Medicine ; Detroit , MI USA.|e Division of Pediatric Hematology/Oncology; Children's Hospital of Michigan ; Detroit , MI USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Taub
authors.affiliation: d Department of Pediatrics ; Wayne State University School of Medicine ; Detroit , MI USA.|e Division of Pediatric Hematology/Oncology; Children's Hospital of Michigan ; Detroit , MI USA.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: f Department of Pediatric Hematology and Oncology; The First Hospital of Jilin University ; Cangchun , China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: f Department of Pediatric Hematology and Oncology; The First Hospital of Jilin University ; Cangchun , China.
authors.forename: Chunhuai
authors.initials: C
authors.lastname: Li
authors.affiliation: g Department of Hematology and Oncology; The First Hospital of Jilin University ; Changchun , China.
authors.forename: Hai
authors.initials: H
authors.lastname: Lin
authors.affiliation: b Department of Oncology ; Wayne State University School of Medicine ; Detroit , MI USA.|c Molecular Therapeutics Program; Barbara Ann Karmanos Cancer Institute; Wayne State University School of Medicine ; Detroit , MI USA.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Ge
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D000077767:Panobinostat; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011744:Pyrimidinones
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D000077767:Panobinostat; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C549567:adavosertib
keywords: Acute myeloid leukemia; CHK1; MK-1775; Panobinostat; Wee1