title: A functional screening of the kinome identifies the Polo-like kinase 4 as a potential therapeutic target for malignant rhabdoid tumors, and possibly, other embryonal tumors of the brain.
abstract: OBJECTIVE
  Malignant rhabdoid tumors (MRTs) are deadly embryonal tumors of the infancy. With poor survival and modest response to available therapies, more effective and less toxic treatments are needed. We hypothesized that a systematic screening of the kinome will reveal kinases that drive rhabdoid tumors and can be targeted by specific inhibitors.
  
  
  METHODS
  We individually mutated 160 kinases in a well-characterized rhabdoid tumor cell line (MON) using lentiviral clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). The kinase that most significantly impaired cell growth was further validated. Its expression was evaluated by microarray gene expression (GE) within 111 pediatric tumors, and functional assays were performed. A small molecule inhibitor was tested in multiple rhabdoid tumor cell lines and its toxicity evaluated in zebrafish larvae.
  
  
  RESULTS
  The Polo-like kinase 4 (PLK4) was identified as the kinase that resulted in higher impairment of cell proliferation when mutated by CRISPR/Cas9. PLK4 CRISPR-mutated rhabdoid cells demonstrated significant decrease in proliferation, viability, and survival. GE showed upregulation of PLK4 in rhabdoid tumors and other embryonal tumors of the brain. The PLK4 inhibitor CFI-400945 showed cytotoxic effects on rhabdoid tumor cell lines while sparing non-neoplastic human fibroblasts and developing zebrafish larvae.
  
  
  CONCLUSIONS
  Our findings indicate that rhabdoid tumor cell proliferation is highly dependent on PLK4 and suggest that targeting PLK4 with small-molecule inhibitors may hold a novel strategy for the treatment of MRT and possibly other embryonal tumors of the brain. This is the first time that PLK4 has been described as a potential target for both brain and pediatric tumors.
authors.affiliation: Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.|Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.|Department of Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute, Chicago, Illinois.
authors.forename: Simone Treiger
authors.initials: ST
authors.lastname: Sredni
authors.affiliation: Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.|Department of Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute, Chicago, Illinois.|Department of Neurosurgery, School of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Mario
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Research and Development, Biosciences Division, Thermo Fisher Scientific, Carlsbad, California.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.|Department of Developmental Biology, Stanley Manne Children's Research Institute, Chicago, Illinois.
authors.forename: Jacek
authors.initials: J
authors.lastname: Topczewski
authors.affiliation: Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.|Department of Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute, Chicago, Illinois.
authors.forename: Anders W
authors.initials: AW
authors.lastname: Bailey
authors.affiliation: Research and Development, Biosciences Division, Thermo Fisher Scientific, Carlsbad, California.
authors.forename: Tufan
authors.initials: T
authors.lastname: Gokirmak
authors.affiliation: Department of Cancer Biology and Epigenomics, Stanley Manne Children's Research Institute, Chicago, Illinois.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Gross
authors.affiliation: Research and Development, Biosciences Division, Thermo Fisher Scientific, Carlsbad, California.
authors.forename: Alexandre
authors.initials: A
authors.lastname: de Andrade
authors.affiliation: Department of Neurosurgery, School of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Kondo
authors.affiliation: Research and Development, Biosciences Division, Thermo Fisher Scientific, Carlsbad, California.
authors.forename: David R
authors.initials: DR
authors.lastname: Piper
authors.affiliation: Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.|Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Tadanori
authors.initials: T
authors.lastname: Tomita
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D064113:CRISPR-Cas Systems / Q000235:genetics*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007814:Larva / Q000254:growth & development / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018335:Rhabdoid Tumor / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016415:Sequence Alignment; D014407:Tumor Cells, Cultured; D015027:Zebrafish / Q000254:growth & development / Q000378:metabolism
chemical_list: C000592365:2-(3-(4-((2,6-dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)-5'-methoxyspiro(cyclopropane-1,3'-indolin)-2'-one; D007191:Indazoles; D007211:Indoles; C490219:PLK4 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: AT/RT; CFI-400495; CRISPR/Cas9; Lentivirus; MRT; PLK4; PLK4i; RTK; gene editing; inhibitor; kinase; kinome; rhabdoid; treatment