Cancer drug - in a different way than expected

Polo-like kinase 1 (PLK1) is overexpressed in a large number of cancers, especially in fast-growing, chromosome-unstable tumors. The enzyme is involved in cell division: It regulates the formation of the division spindle and the correct distribution of chromosomes among the daughter cells. High PLK1 levels are associated with an unfavorable prognosis in many cancers, which is why PLK1 is considered a classic oncogene.

A blockage of PLK1 results in incorrectly distributed chromosomes, stop of the cell cycle, and finally in cell death. The enzyme is therefore regarded as a promising target structure for new cancer drugs. However, there are also contradictory results on the role of PLK1 in carcinogenesis. Other studies have shown that high PLK1 expression is even associated with a better prognosis in certain forms of breast cancer. "So far, little information has been available on how high PLK1 levels could contribute to the transformation of cells and the development of cancer," said Rocio Sotillo from the German Cancer Research Center (DKFZ).

Sotillo and her team have now succeeded in using molecular biological methods to generate mice whose PLK1 production can be stimulated "from the outside" via a regulator in the food. Using these animals, the researchers investigated the effects of high PLK1 levels on cell division and tumor development. They discovered that the normal distribution of chromosomes into the two daughter cells is disturbed in the PLK1 overexpressing cells. In addition, the daughter cells could not completely separate from each other, which led to cells with two or even four nuclei.

Overexpression of PLK1 led to an 85 percent reduction in breast tumors in mice that would normally have developed breast cancer due to a strong oncogene (Kras or Her2). The few tumors that developed despite PLK1 overexpression were significantly delayed.

"From these results we conclude that PLK1 is not an oncogene, but rather has tumor-suppressive properties," said Rocio Sotillo. Several inhibitors that block the activity of PLK1 are currently undergoing clinical trials. "However, our results do not necessarily speak against the use of such PLK1 inhibitors in cancer therapy. Many important components of the cell division apparatus are suitable as targets for innovative treatment approaches because the tumor cells are extremely dependent on these structures," explains the tumor biologist and adds: "Therefore, PLK1 inhibitors could prove to be useful cancer drugs - only under different conditions than previously thought!"

Guillermo de Cárcer, Sharavan Vishaan Venkateswaran, Lorena Salgueiro, Aicha El Bakkali, Kalman Somogyi, Konstantina Rowald, Pablo Montañes, Manuel Sanclemente, Beatriz Escobar, Alba de Martino, Nicholas McGranahan, Marcos Malumbres und Rocío Sotillo: Plk1 overexpression induces chromosomal instability and suppresses tumor development.
Nature Communications 2018, DOI: 10.1038/s41467-018-05429-5