The CINs of Polo-Like Kinase 1 in Cancer

SIMPLE SUMMARY: Many alterations specific to cancer cells have been investigated as targets for targeted therapies. Chromosomal instability is a characteristic of nearly all cancers that can limit response to targeted therapies by ensuring the tumor population is not genetically homogenous. Polo-like Kinase 1 (PLK1) is often up regulated in cancers and it regulates chromosomal instability extensively. PLK1 has been the subject of much pre-clinical and clinical studies, but thus far, PLK1 inhibitors have not shown significant improvement in cancer patients. We discuss the numerous roles and interactions of PLK1 in regulating chromosomal instability, and how these may provide an avenue for identifying targets for targeted therapies. As selective inhibitors of PLK1 showed limited clinical success, we also highlight how genetic interactions of PLK1 may be exploited to tackle these challenges. 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.