Abstract
BackgroundPolo-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.ResultsTreatment 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.DiscussionThese results support the further investigation of PLK4 as a drug target in pancreatic cancer.MethodsSensitivity 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.
Highlights
The genomic landscape of pancreatic cancer is dominated by a high prevalence of mutations involving K-Ras, p53, SMAD4, and p16 [1, 2], none of which is readily targetable using currently available agents
Consistent with Polo-like kinase 4 (PLK4) inhibition, we observed reduced expression of the proliferation marker Ki-67 associated with an increase in nuclear diameter during treatment with CFI-400945
These results support the further investigation of PLK4 as a drug target in pancreatic cancer
Summary
The genomic landscape of pancreatic cancer is dominated by a high prevalence of mutations involving K-Ras, p53, SMAD4, and p16 [1, 2], none of which is readily targetable using currently available agents. It has been suggested that chromosomal instability causes vulnerability to agents that disrupt orderly movement through the late cell cycle, suggesting a novel approach to the treatment of these highly lethal cancers. Polo-like kinase 4 (PLK4) plays a unique role in centriole regulation [8]. CFI-400945 is a potent PLK4 inhibitor that is currently undergoing a phase I clinical trial [9, 10, 11]. In the present study we tested CFI-400945 for activity in a series of orthotopically-grown, patient-derived pancreatic cancer xenografts, selected to represent the range of genetic and growth characteristics seen in the clinic. CFI-400945 is a first in class small molecule PLK4 inhibitor, currently undergoing early phase clinical trials
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