ZFIN ID: ZDB-PUB-170412-1
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
Sredni, S.T., Suzuki, M., Yang, J.P., Topczewski, J., Bailey, A.W., Gokirmak, T., Gross, J.N., de Andrade, A., Kondo, A., Piper, D.R., Tomita, T.
Date: 2017
Source: Pediatric blood & cancer   64(11): (Journal)
Registered Authors: Gross, Jeffrey, Topczewski, Jacek
Keywords: AT/RT, CFI-400495, CRISPR/Cas9, Lentivirus, MRT, PLK4, PLK4i, RTK, gene editing, inhibitor, kinase, kinome, rhabdoid, treatment
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • Brain Neoplasms/drug therapy*
  • Brain Neoplasms/genetics
  • Brain Neoplasms/pathology
  • CRISPR-Cas Systems/genetics*
  • Cell Cycle/drug effects
  • Cell Proliferation/drug effects
  • High-Throughput Screening Assays/methods*
  • Humans
  • Indazoles/pharmacology*
  • Indoles/pharmacology*
  • Larva/growth & development
  • Larva/metabolism
  • Mutation/genetics
  • Protein-Serine-Threonine Kinases/antagonists & inhibitors
  • Protein-Serine-Threonine Kinases/genetics
  • Protein-Serine-Threonine Kinases/metabolism*
  • Rhabdoid Tumor/drug therapy*
  • Rhabdoid Tumor/genetics
  • Rhabdoid Tumor/pathology
  • Sequence Alignment
  • Tumor Cells, Cultured
  • Zebrafish/growth & development
  • Zebrafish/metabolism
PubMed: 28398638 Full text @ Pediatr Blood Cancer
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ABSTRACT
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.
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.
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.
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.
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