Abstract
Simple SummaryMany 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.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.
Highlights
Tumor heterogeneity and an increased rate of genetic mutations are prevalent features of cancer that need to be addressed in therapy to prevent treatment resistance and improve patient outcomes.Cancers 2020, 12, 2953; doi:10.3390/cancers12102953 www.mdpi.com/journal/cancersTumor heterogeneity refers to the presence of multiple distinct genotypes and phenotypes within the tumor cell population
forkhead box protein M1 (FoxM1) expression begins to increase in S phase and is phosphorylated by Cyclin B/CDK1 and Polo-like kinase 1 (PLK1) to increase its transcriptional activity of mitotic targets, such as AURKB, cyclin B, and PLK1 itself, in a positive feedback loop in preparation to irreversibly commit cells to mitotic entry [33]
PLK1 itself is an attractive target for the development of cancer therapeutics because there is a mass of evidence indicating that it is highly overexpressed selectively in tumor cells compared to the healthy adult tissues
Summary
Tumor heterogeneity and an increased rate of genetic mutations are prevalent features of cancer that need to be addressed in therapy to prevent treatment resistance and improve patient outcomes. PLK1 and AURKB signaling initiates cytokinesis [22] Working in concert, these kinases regulate a multitude of cell cycle checkpoints, effector proteins, and each other and their deregulation is associated with multiple malignancies [13,23]. These kinases regulate a multitude of cell cycle checkpoints, effector proteins, and each other and their deregulation is associated with multiple malignancies [13,23] Many of these molecules have been found to be overexpressed in tumor cells and have been put forward as potential therapeutic targets, including CDK1 [24], NEK2 [25], AURKA [26], Bub1 [27], and TTK [28].
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