The concept of targeting mitotic cell division to halt the progression of rapidly dividing cancer cells has long been a staple of oncology therapy, yet chemotherapy agents that are the prime examples of this approach are nonselective in their action and can kill normal and malignant cells alike. Now, novel targeted approaches focusing on the inhibition of mitotic kinases are showing significant promise.
Among them are agents targeting polo-like kinase 1 (Plk1), which plays an important role throughout mitosis. Despite some clinical disappointment, a greater understanding of the intricate molecular mechanisms underlying the progression of the cell cycle and the respective roles of the PLK kinase family has offered renewed hope.
The lead agent in this category is volasertib, which has achieved breakthrough therapy and orphan drug designations from the FDA, and expectations are high for late-stage clinical testing that may result in the first approved agent in this class.
Rationale for Focusing on PLK
One of the hallmarks of cancer is unchecked cell division and, as such, targeting mitosis in these rapidly dividing cells has become a validated therapeutic approach. In recent years, researchers have identified various “checkpoints” that ensure cell division occurs at the appropriate time—and that may become dysregulated in human cancers.
Many of these checkpoints are controlled by protein kinases, among them the PLKs, a family of serine/threonine kinases. There are five members of the PLK family: Plks 1 through 5. Although they have different functions and tissue locations, most share a similar structure. At one end of the protein is the serine/threonine kinase domain (except for Plk5 which seems to lack a functional kinase domain) that is responsible for catalytic activity, while at the other end is a polo-box domain (PBD). The PBD is a regulatory domain that controls kinase activity; it prevents the kinase domain from binding to its target proteins until it receives the appropriate activation signal.
Plk1 is the most well characterized member of the family. The Plk1 protein is only expressed in dividing cells and its levels fluctuate during the course of the cell cycle. Its activity peaks during mitosis (M) phase, where it is involved in almost every step of mitotic cell division via the phosphorylation of a wide variety of downstream targets, including cyclin B1 and CDC25, which trigger entry into mitosis. Plk1 also regulates other mitotic events such as spindle formation and chromosome segregation.
Mitotic Roles of Plk1
Polo-like kinase 1 (Plk1) is activated throughout the process of mitotic regulation and cell division, with its peak expression during the G2/M phase of the cycle, as illustrated above.
G1 indicates growth 1 phase of the cell cycle; G2, growth 2; M, mitosis.
Donaldson MM, et al. The mitotic roles of polo-like kinase. J Cell Sci. 2001;114(13):2357-2358. jcs.biologists.org. Adapted with permission.
Plk1 and other mitotic kinases act as cell cycle checkpoints, so that entry into mitosis and subsequent cell division and proliferation is prevented in the absence of appropriate signals. High levels of Plk1 essentially permit the cancer cell to pass through these checkpoints unimpeded, contributing to the hallmark unchecked cell division and proliferation observed in tumors. Although evidence that Plk1 as an oncogene is lacking, it is frequently overexpressed in many different cancer types, including non–small cell lung cancer (NSCLC), melanoma, colorectal carcinoma, and prostate cancer, and high levels of Plk1 expression often correlate with poor prognosis.
The cellular roles of the other PLKs are less clear. However, several studies have suggested that Plk2 and Plk3 may in fact have opposing functions to the proliferative role of Plk1 and act as tumor suppressors or at the very least have functions that are unrelated to cancer cell proliferation. The PLK2 gene has been shown to be frequently methylated and silenced in B cell malignancies, while reduced expression of Plk3 proteins has been observed in several cancer types.
Since Plk1 is highly expressed in cancer cells, but not in nondividing healthy cells, it represents an attractive means to target mitosis in a more specific manner than chemotherapeutics. There has been significant research and development in this area and a number of Plk1-targeting agents have been investigated.
Volasertib Leads the Class
A common method of inhibiting protein kinases is to develop compounds that target the adenosine triphosphate (ATP) binding site. As the name implies, these ATP-competitive inhibitors compete with ATP for binding to the kinase and thus prevent its activation. The first Plk1 inhibitors were designed, as such, to be ATP-competitive inhibitors.