title: Synergistic antitumor interactions between MK-1775 and panobinostat in preclinical models of pancreatic cancer.
abstract: Pancreatic cancer remains a clinical challenge, thus new therapies are urgently needed. The selective Wee1 inhibitor MK-1775 has demonstrated promising results when combined with DNA damaging agents, and more recently with CHK1 inhibitors in various malignancies. We have previously demonstrated that treatment with the pan-histone deacetylase inhibitor panobinostat (LBH589) can cause down-regulation of CHK1. Accordingly, we investigated using panobinostat to down-regulate CHK1 in combination with MK-1775 to enhance cell death in preclinical pancreatic cancer models. We demonstrate that MK-1775 treatment results in increased H2AX phosphorylation, indicating increased DNA double-strand breaks, and activation of CHK1, which are both dependent on CDK activity. Combination of MK-1775 and panobinostat resulted in synergistic antitumor activity in six pancreatic cancer cell lines. Finally, our in vivo study using a pancreatic xenograft model reveals promising cooperative antitumor activity between MK-1775 and panobinostat. Our study provides compelling evidence that the combination of MK-1775 and panobinostat has antitumor activity in preclinical models of pancreatic cancer and supports the clinical development of panobinostat in combination with MK-1775 for the treatment of this deadly disease.
authors.affiliation: 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; Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Guan
authors.initials: G
authors.lastname: Wang
authors.affiliation: 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: Xiaojia
authors.initials: X
authors.lastname: Niu
authors.affiliation: 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: MD/PhD Program, Wayne State University School of Medicine, Detroit, MI, USA; Cancer Biology Program, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: J Timothy
authors.initials: JT
authors.lastname: Caldwell
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: Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, 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; 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 Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China. Electronic address: zhao_lj@jlu.edu.cn.
authors.forename: Lijing
authors.initials: L
authors.lastname: Zhao
authors.affiliation: 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; 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. Electronic address: gey@karmanos.org.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Ge
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects; D004347:Drug Interactions; D004357:Drug Synergism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077767:Panobinostat; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011744:Pyrimidinones; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D009687:Nuclear Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000077767:Panobinostat; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C549567:adavosertib
keywords: CHK1; Drug combination; MK-1775; Pancreatic cancer; Panobinostat