PLK1: A Mitotic Kinase and Its Role in Cancer

A Kinase That Works Throughout Mitosis

PLK1 helps trigger mitotic entry by activating the CDC25 phosphatases and promoting nuclear accumulation of cyclin B, reinforcing CDK1 activation.

It then acts at centrosomes to support their maturation and separation, at kinetochores to help establish stable attachments, and at the central spindle and midbody to drive cytokinesis. Few other kinases are needed at so many steps.

Why It Is Overexpressed in Cancer

High PLK1 expression is reported across lung, breast, colorectal, prostate and other cancers and often correlates with proliferation rate and, in some series, with worse prognosis.

Rapidly dividing cells simply require more mitotic kinase activity, so PLK1 elevation is partly a consequence of proliferation rather than always a driver.

The Tumour-Suppressor Side

PLK1 also participates in recovery from the DNA-damage checkpoint and interacts with p53, and some mouse models show that reduced Plk1 gene dosage can increase tumour incidence.

This context dependence means PLK1 is not a straightforward oncogene, and the effect of inhibiting it may differ between tumours with and without intact p53.

PLK1 Inhibitors

ATP-competitive inhibitors such as volasertib and onvansertib block PLK1 activity and cause mitotic arrest followed by death. Volasertib reached phase 3 in acute myeloid leukaemia without gaining approval; onvansertib is in trials, including in KRAS-mutant colorectal cancer combinations.

Neutropenia is the main dose-limiting toxicity, reflecting the sensitivity of dividing bone-marrow cells.

Interpretation Notes

A high-PLK1 result in expression profiling is a proliferation-associated marker and is not a validated biomarker for selecting PLK1-inhibitor therapy.

As with Aurora kinases, most of the clinical rationale currently rests on tumour context and combination partners rather than a single-gene test.

Key Takeaways

• ·PLK1 acts at mitotic entry, centrosomes, kinetochores and cytokinesis.
• ·Overexpression is common in cancer and partly reflects high proliferation.
• ·PLK1 has a context-dependent tumour-suppressor role linked to p53 and checkpoint recovery.
• ·Inhibitors such as onvansertib remain investigational, with neutropenia the key toxicity.