The CINs of Polo-Like Kinase 1 in Cancer

Abstract

Polo-like kinase 1 (PLK1) is overexpressed near ubiquitously across all cancer types and dysregulation of this enzyme is closely tied to increased chromosomal instability and tumor heterogeneity. PLK1 is a mitotic kinase with a critical role in maintaining chromosomal integrity through its function in processes ranging from the mitotic checkpoint, centrosome biogenesis, bipolar spindle formation, chromosome segregation, DNA replication licensing, DNA damage repair, and cytokinesis. The relation between dysregulated PLK1 and chromosomal instability (CIN) makes it an attractive target for cancer therapy. However, clinical trials with PLK1 inhibitors as cancer drugs have generally displayed poor responses or adverse side-effects. This is in part because targeting CIN regulators, including PLK1, can elevate CIN to lethal levels in normal cells, affecting normal physiology. Nevertheless, aiming at related genetic interactions, such as synthetic dosage lethal (SDL) interactions of PLK1 instead of PLK1 itself, can help to avoid the detrimental side effects associated with increased levels of CIN. Since PLK1 overexpression contributes to tumor heterogeneity, targeting SDL interactions may also provide an effective strategy to suppressing this malignant phenotype in a personalized fashion.

Keywords: DNA damage repair; Polo-like kinase 1; chromosomal instability; synthetic dosage lethality.

Figure 1

Mitotic kinases that are involved in cancer. (A). Differential expression of mitotic kinases across cancer types as analyzed from TCGA data. Green color indicates higher expression in cancer. (B). A schematic representation of PLK1 structure. This includes the Ser/Thr kinase domain, the linker region, and PBD. Activating phosphorylation at residues T210 and S137 is required catalytic activity. The D-box is the site for signaling for proteasome degradation. NLS targets PLK1 into the nucleus, while PBD targets PLK1 to the centrosome, substrates and functional partners.