Activity of the novel polo-like kinase 4 inhibitor CFI-400945 in pancreatic cancer patient-derived xenografts

I. Lohse, J. M. Mason, P. J. Cao, Melania Pintilie, M. R. Bray, D. W. Hedley

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Background: Polo-like kinase 4 (PKL4) plays a key role in centriole replication. Hence PLK4 inhibition disrupts mitosis, and offers a novel approach to treating chromosomally unstable cancers, including pancreatic cancer. CFI-400945 is a first in class small molecule PLK4 inhibitor, currently undergoing early phase clinical trials. Results: Treatment with CFI-400945 significantly reduced tumor growth and increased survival in four out of the six models tested. Consistent with PLK4 inhibition, we observed reduced expression of the proliferation marker Ki-67 associated with an increase in nuclear diameter during treatment with CFI-400945. Additionally, treatment with CFI-400945 resulted in a significant reduction of tumor-initiating cells. Discussion: These results support the further investigation of PLK4 as a drug target in pancreatic cancer. Methods: Sensitivity to CFI-400945 was tested in a series of six patientderived pancreatic cancer xenografts, selected to represent the range of growth characteristics, genetic features, and hypoxia found in pancreatic cancer patients.

Original languageEnglish (US)
Pages (from-to)3064-3071
Number of pages8
JournalOncotarget
Volume8
Issue number2
DOIs
StatePublished - 2017
Externally publishedYes

Keywords

  • CFI-400945
  • Pancreatic cancer
  • Patient-derived pancreatic cancer xenografts
  • PLK4
  • Polo-like kinase 4

ASJC Scopus subject areas

  • Oncology

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