DNA-PKcs Emerges as Master Driver of Metastasis

A new study demonstrates that the DNA repair kinase DNA-PKcs plays an unexpected role in cell migration and invasion, and that it may serve as a biomarker for predicting development of metastatic prostate cancer. The findings suggest that the molecule may be a promising therapeutic target to prevent metastases in prostate and other cancers.

In the study, published in Cancer Cell, researchers discovered high expression and activity levels of DNA-PKcs, the catalytic subunit of the protein kinase complex DNA-PK, in human samples of advanced prostate cancer. They then administered a DNA-PKcs inhibitor to xenograft mouse models and found that it suppressed pathways that promote cell migration and invasion. Finally, they conducted a retrospective analysis of 232 samples from patients with high-risk localized prostate cancer and found that those who developed metastatic disease had high DNA-PKcs expression.

“This study shows that DNA-PKcs has a highly unanticipated role in promoting the ability of cells not only to repair DNA but also to move and migrate,” says the study's lead author Karen Knudsen, PhD, director of the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, PA. “This kinase that is so highly expressed in advanced disease is promoting lethal events that may be preventable by pharmacologically targeting DNA-PKcs.”

The findings lay the foundation for a planned phase Ib expansion/phase II trial of the DNA-PKcs inhibitor CC-115 (Celgene) in combination with enzalutamide (Xtandi; Astellas/Medivation), an androgen-receptor (AR) inhibitor, in men with metastatic prostate cancer, says Knudsen.

In previous research, Knudsen and her colleagues showed that DNA-PK works in concert with the AR, which plays an important role in regulating many genes involved in metastatic growth, including the gene encoding DNA-PKcs. Their findings suggest that targeting both AR activity and DNA-PKcs may be an effective way of treating hormone-refractory metastatic prostate cancer.

“These new findings support the idea that it is the direct function of DNA-PKcs on the expression of genes that is important for the metastatic process,” says Myles Brown, MD, director of the Center for Functional Cancer Epigenetics at Dana-Farber Cancer Institute in Boston, MA, who was not involved with the study. “That's important therapeutically because there has been a huge amount of progress recently in developing highly specific kinase inhibitors for a wide range of cancers.”

Because DNA-PK is known to be highly active in a variety of tumor types, the new findings may have implications for developing treatments for other types of cancer as well, says Knudsen.

However, Brown notes that although DNA-PKcs inhibitors appear to prevent the metastatic process, there is no evidence that they can stop the process once it has started. That's particularly relevant for prostate cancer, which, unlike breast cancer, does not have an established window in which to administer adjuvant therapy to prevent metastatic disease.

“This is a study that supports the development of DNA-PKcs inhibitors to prevent metastatic spread,” he says. “It provides preclinical rationale to pursue that line of clinical investigation.”