title: CK2 blockade causes MPNST cell apoptosis and promotes degradation of β-catenin.
abstract: Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that are a major cause of mortality of Neurofibromatosis type 1 (NF1) patients. MPNST patients have few therapeutic options available and only complete surgical resection can be curative. MPNST formation and survival are dependent on activated β-catenin signaling. The goal of this study was to determine if inhibition of the CK2 enzyme can be therapeutically exploited in MPNSTs, given CK2's role in mainta ining oncogenic phenotypes including stabilization of β-catenin. We found that CK2α is over-expressed in MPNSTs and is critical for maintaining cell survival, as the CK2 inhibitor, CX-4945 (Silmitasertib), and shRNA targeting CK2α each significantly reduce MPNST cell viability. These effects were preceded by loss of critical signaling pathways in MPNSTs, including destabilization of β-catenin and TCF8. CX-4945 administration in vivo slowed tumor growth and extends survival time. We conclude that CK2 inhibition is a promising approach to blocking β-catenin in MPNST cells, although combinatorial therapies may be required for maximal efficacy.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Jed J
authors.initials: JJ
authors.lastname: Kendall
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Chaney
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Ami V
authors.initials: AV
authors.lastname: Patel
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Tilat A
authors.initials: TA
authors.lastname: Rizvi
authors.affiliation: Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004159:Diphenylamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008819:Mice, Nude; D009287:Naphthyridines / Q000008:administration & dosage / Q000494:pharmacology*; D018317:Nerve Sheath Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010619:Phenazines; D059748:Proteolysis / Q000187:drug effects; D034622:RNA Interference; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D001549:Benzamides; D009287:Naphthyridines; D010619:Phenazines; D051176:beta Catenin; C506614:mirdametinib; D004159:Diphenylamine; C555142:silmitasertib; D047390:Casein Kinase II
keywords: CK2; G2 arrest; MPNST; NF1; β-catenin