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

Ines Lohse; Jacqueline Mason; Pinjiang Mary Cao; Melania Pintilie; Mark Bray; David W. Hedley

doi:10.18632/oncotarget.13619

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Research Papers:

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

Ines Lohse _, Jacqueline Mason, Pinjiang Mary Cao, Melania Pintilie, Mark Bray and David W. Hedley

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Oncotarget. 2017; 8:3064-3071. https://doi.org/10.18632/oncotarget.13619

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Abstract

Ines Lohse1, Jacqueline Mason1, Pinjiang Mary Cao1, Melania Pintilie1, Mark Bray1, David W. Hedley1,2

1Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

2Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada

Correspondence to:

David W. Hedley, email: [email protected]

Keywords: polo-like kinase 4, PLK4, CFI-400945, pancreatic cancer, patient-derived pancreatic cancer xenografts

Received: August 15, 2016 Accepted: October 24, 2016 Published: November 25, 2016

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.

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PII: 13619

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Research Papers:

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

Abstract