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

Abstract

BACKGROUND:

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.

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 patient-derived pancreatic cancer xenografts, selected to represent the range of growth characteristics, genetic features, and hypoxia found in pancreatic cancer patients.

• Authors: Ines Lohse, Jacqueline Mason, Pinjiang Mary Cao, Melania Pintilie, Mark Bray, David W Hedley
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 2 Pg. 3064-3071 (Jan 10 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 27902970 (Publication Type: Journal Article)

Chemical References

• 2-(3-(4-((2,6-dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)-5'-methoxyspiro(cyclopropane-1,3'-indolin)-2'-one
• Antineoplastic Agents
• Biomarkers, Tumor
• Indazoles
• Indoles
• Protein Kinase Inhibitors
• PLK4 protein, human
• Protein Serine-Threonine Kinases

Topics

• 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, metabolism)
• Pancreatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• Tumor Burden
• Xenograft Model Antitumor Assays