title: Inhibition of CHK1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells.
abstract: Resistance to standard chemotherapy agents remains a major obstacle for improving treatment outcomes for acute myeloid leukemia (AML). The Bcl-2-selective inhibitor ABT-199 has demonstrated encouraging preclinical results, drug resistance remains a concern. Mcl-1 has been demonstrated to contribute to ABT-199 resistance, thus combining with therapies that target Mcl-1 could overcome such resistance. In this study, we utilized a CHK1 inhibitor, LY2603618, to decrease Mcl-1 and enhance ABT-199 efficacy. We found that LY2603618 treatment resulted in abolishment of the G2/M cell cycle checkpoint and increased DNA damage, which was partially dependent on CDK activity. LY2603618 treatment resulted in decrease of Mcl-1, which coincided with the initiation of apoptosis. Overexpression of Mcl-1 in AML cells significantly attenuated apoptosis induced by LY2603618, confirming the critical role of Mcl-1 in apoptosis induced by the agent. Simultaneous treatment with LY2603618 and ABT-199 resulted in synergistic induction of apoptosis in both AML cell lines and primary patient samples. Our findings provide new insights into overcoming a mechanism of intrinsic ABT-199 resistance in AML cells and support the clinical development of combined ABT-199 and CHK1 inhibition.
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, School of Life Sciences, Jilin University, Changchun, China.|Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA.
authors.forename: Jianyun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, School of Life Sciences, Jilin University, Changchun, China.
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Niu
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, School of Life Sciences, Jilin University, Changchun, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.|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: National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, School of Life Sciences, Jilin University, Changchun, China.
authors.forename: Guan
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Pediatric Hematology and Oncology, The First Hospital of Jilin University, Changchun, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.|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: Department of Hematology and Oncology, The First Hospital of Jilin University, Changchun, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.|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*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors*; D004249:DNA Damage / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008938:Mitosis / Q000187:drug effects; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D000074084:THP-1 Cells; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C582547:LY2603618; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D013449:Sulfonamides; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C579720:venetoclax
keywords: ABT-199; CHK1; LY2603618; Mcl-1; acute myeloid leukemia