Inhibition of polo-like kinase 4 (PLK4): A new therapeutic option for rhabdoid tumors and pediatric medulloblastoma

Simone Treiger Sredni*, Anders W. Bailey, Amreena Suri, Rintaro Hashizume, Xingyao He, Nundia Louis, Tufan Gokirmak, David R. Piper, Daniel M. Watterson, Tadanori Tomita

*Corresponding author for this work

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Rhabdoid tumors (RT) are highly aggressive and vastly unresponsive embryonal tumors. They are the most common malignant CNS tumors in infants below 6 months of age. Medulloblastomas (MB) are embryonal tumors that arise in the cerebellum and are the most frequent pediatric malignant brain tumors. Despite the advances in recent years, especially for the most favorable molecular subtypes of MB, the prognosis of patients with embryonal tumors remains modest with treatment related toxicity dreadfully high. Therefore, new targeted therapies are needed. The polo-like kinase 4 (PLK4) is a critical regulator of centriole duplication and consequently, mitotic progression. We previously established that PLK4 is overexpressed in RT and MB. We also demonstrated that inhibiting PLK4 with a small molecule inhibitor resulted in impairment of proliferation, survival, migration and invasion of RT cells. Here, we showed in MB the same effects that we previously described for RT. We also demonstrated that PLK4 inhibition induced apoptosis, senescence and polyploidy in RT and MB cells, thereby increasing the susceptibility of cancer cells to DNAdamaging agents. In order to test the hypothesis that PLK4 is a CNS druggable target, we demonstrated efficacy with oral administration to an orthotropic xenograft model. Based on these results, we postulate that targeting PLK4 with small-molecule inhibitors could be a novel strategy for the treatment of RT and MB and that PLK4 inhibitors (PLK4i) might be promising agents to be used solo or in combination with cytotoxic agents.

Original languageEnglish (US)
Pages (from-to)111190-111212
Number of pages23
JournalOncotarget
Volume8
Issue number67
DOIs
StatePublished - Jan 1 2017

Keywords

  • AT/RT
  • Embryonal tumors
  • Medulloblastoma
  • PLK4
  • Rhabdoid

ASJC Scopus subject areas

  • Oncology

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