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

Polo-like kinase 4 (PLK4) 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 p...

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Bibliographic Details
Published in:Oncotarget 2017-01, Vol.8 (2), p.3064-3071
Main Authors: Lohse, Ines, Mason, Jacqueline, Cao, Pinjiang Mary, Pintilie, Melania, Bray, Mark, Hedley, David W
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Biomarkers, Tumor
Cell Line, Tumor
Cell Proliferation
Disease Models, Animal
Humans
Immunohistochemistry
Indazoles - pharmacology
Indoles - pharmacology
Mice
Neoplastic Stem Cells - drug effects
Neoplastic Stem Cells - metabolism
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Protein Kinase Inhibitors - pharmacology
Protein Serine-Threonine Kinases - antagonists & inhibitors
Protein Serine-Threonine Kinases - genetics
Protein Serine-Threonine Kinases - metabolism
Research Paper
Tumor Burden
Xenograft Model Antitumor Assays
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Summary:Polo-like kinase 4 (PLK4) 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. 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. These results support the further investigation of PLK4 as a drug target in pancreatic cancer. Sensitivity to CFI-400945 was tested in a series of six patient-derived pancreatic cancer xenografts, selected to represent the range of growth characteristics, genetic features, and hypoxia found in pancreatic cancer patients.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.13619