Present and Future Perspective on PLK1 Inhibition in Cancer Treatment

Abstract

Polo-like kinase 1 (PLK1) is the principle member of the well conserved serine/threonine kinase family. PLK1 has a key role in the progression of mitosis and recent evidence suggest its important involvement in regulating the G2/M checkpoint, in DNA damage and replication stress response, and in cell death pathways. PLK1 expression is tightly spatially and temporally regulated to ensure its nuclear activation at the late S-phase, until the peak of expression at the G2/M-phase. Recently, new roles of PLK1 have been reported in literature on its implication in the regulation of inflammation and immunological responses. All these biological processes are altered in tumors and, considering that PLK1 is often found overexpressed in several tumor types, its targeting has emerged as a promising anti-cancer therapeutic strategy. In this review, we will summarize the evidence suggesting the role of PLK1 in response to DNA damage, including DNA repair, cell cycle progression, epithelial to mesenchymal transition, cell death pathways and cancer-related immunity. An update of PLK1 inhibitors currently investigated in preclinical and clinical studies, in monotherapy and in combination with existing chemotherapeutic drugs and targeted therapies will be discussed.

Construction of a Colorectal Cancer Prognostic Risk Model and Screening of Prognostic Risk Genes Using Machine-Learning Algorithms

“…PLK1 overexpression has been observed in many types of tumors, and therefore, PLK1 has long been considered as an oncogene [ 30 ]. However, the oncogenic properties of PLK1 have not been confirmed [ 31 , 32 ]. In a study by de Cárcer et al that was published in Nature Communications, PLK1 was speculated to act as a tumor suppressor rather than as an oncogene [ 33 ].…”

UBAP2L-dependent coupling of PLK1 localization and stability during mitosis

“…Phosphorylation and ubiquitylation pathways are tightly interconnected in mitosis and it is important to understand these links in the context of carcinogenesis. PLK1 is misregulated in human cancers and small molecule inhibitors targeting PLK1 are currently being explored for cancer treatment (Chiappa et al, 2022). However, preclinical success with currently available PLK1 inhibitors has not translated well into clinical success, highlighting the need for a complete understanding of upstream PLK1 regulatory mechanisms.…”

“…Protein kinases represent key regulatory elements of the mitotic cycle, transferring phosphorylation signals to critical effectors (Nigg, 2001). Polo-like kinase 1 (PLK1) represents one of the key mitotic enzymes ensuring both mitotic entry as well as fidelity of genome segregation, mitotic exit and cytokinesis (Schmucker and Sumara, 2014; Combes et al, 2017; Petronczki et al, 2008) and remains an attractive target for anticancer therapies (Chiappa et al, 2022; Strebhardt, 2010). PLK1 is a serine/threonine kinase with an enzymatic domain at its N-terminal and a Polo-Box domain (PBD) at its C-terminal part, the latter representing a unique feature of the PLK kinase family and conferring specificity to phosphorylation substrates (Strebhardt, 2010; Barr et al, 2004; Zitouni et al, 2014).…”

Polo-like kinase 1 as a potential therapeutic target and prognostic factor for various human malignancies: A systematic review and meta-analysis

“…PLK-1 inhibition, in combination with other targeted drugs such as cisplatin and paclitaxel, has thus become a new strategy for the treatment of malignant tumors. (6) This phenomenon indicates that PLK-1 is widely present in various types of tumors, suggesting that it will be a clinically valuable therapeutic target.…”

“…PLK-1 is key for cell division, mitotic progression, and DNA damage repair ( 4 , 5 ). In addition, recent research has found that PLK-1 is also related to epithelial–mesenchymal transition, cell death, and the immune system ( 6 ). This protein kinase is differentially expressed in a variety of human cancers, and an increasing number of studies have shown that PLK-1 overexpression is associated with tumor progression and patient prognosis ( 7 ).…”