Cunningham Chelsea E, MacAuley Mackenzie J, Vizeacoumar Frederick S, Abuhussein Omar, Freywald Andrew, Vizeacoumar Franco J
Department of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
College of Pharmacy, University of Saskatchewan, 104 Clinic Place, Saskatoon, SK S7N 2Z4, Canada.
Cancers (Basel). 2020 Oct 13;12(10):2953. doi: 10.3390/cancers12102953.
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.
Polo样激酶1（PLK1）在几乎所有癌症类型中均普遍过表达，该酶的失调与染色体不稳定性增加和肿瘤异质性密切相关。PLK1是一种有丝分裂激酶，通过在有丝分裂检查点、中心体生物发生、双极纺锤体形成、染色体分离、DNA复制许可、DNA损伤修复和胞质分裂等过程中的作用，在维持染色体完整性方面发挥关键作用。PLK1失调与染色体不稳定性（CIN）之间的关系使其成为癌症治疗的一个有吸引力的靶点。然而，以PLK1抑制剂作为癌症药物的临床试验通常显示出疗效不佳或有不良副作用。部分原因是靶向包括PLK1在内的CIN调节因子会使正常细胞中的CIN升高到致死水平，影响正常生理功能。尽管如此，针对相关基因相互作用，如PLK1的合成剂量致死（SDL）相互作用而非PLK1本身，可以帮助避免与CIN水平升高相关的有害副作用。由于PLK1过表达导致肿瘤异质性，靶向SDL相互作用也可能提供一种以个性化方式抑制这种恶性表型的有效策略。
