Polo-Like Kinase 4’s Critical Role in Cancer Development and Strategies for Plk4-Targeted Therapy

Zhang, Xiaoyang; Cheng, Wei; Liang, Hao; Han, Lei

doi:10.3389/fonc.2021.587554

Cited by 38 publications

(62 citation statements)

References 238 publications

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“…PLK4 substrates are not restricted to centriolar-associated networks but a multiplicity of potential target substrates point to participation in non-centriolar signaling networks [94]. PLK4 interacts with a variety of proteins including p53 and nuclear factor kappa B (NFҡB) affecting its expression, stability and activity (reviewed by [10,89]). PLK5 (also known as PLK-5, PLK5P, and SgK384ps) is less explored but unique member of the family as it lacks typical kinase activity due to a truncated kinase domain [95].…”

Section: Polo-like Kinases and Their Physiological Functionsmentioning

confidence: 99%

“…The protein is quickly degraded (reviewed by [ 26 ]). PLK4 is essential for centriole biogenesis driving centriole duplication and mitotic progression [ 84 , 85 , 86 , 87 ], for reviews see [ 6 , 10 , 11 , 47 , 88 , 89 ]. Like PLK1, PLK4 acts as an integrative protein involved in the control of cell division.…”

Section: Polo-like Kinases and Their Physiological Functionsmentioning

confidence: 99%

“…As accounts for PLK1 , PLK4 is overexpressed in a variety of solid tumors and hematologic malignancies considered to act as an oncogene (for reviews see [ 11 , 89 ]). High levels of PLK4 correlate with tumor growth, aggressive progression and treatment resistance representing a poor-prognostic marker.…”

Section: Plks and Tumor Developmentmentioning

confidence: 99%

“…High levels of PLK4 correlate with tumor growth, aggressive progression and treatment resistance representing a poor-prognostic marker. This accounts for a variety of malignancies including several epithelial cancer types (reviewed by [ 11 , 89 ]) such as breast cancer [ 196 , 197 , 198 , 199 ], lung cancer [ 200 , 201 ], prostate cancer [ 202 ], and gastric cancer [ 203 , 204 ], but also for neuroblastoma [ 205 ], glioblastoma [ 206 ], and acute leukemia [ 207 , 208 ]. In skin epidermis, overexpression of PLK4 leads to hyperplasia [ 209 ] and promotes—in association with p53 deficiency—tumorigenesis causing hyperproliferation and abnormal differentiation of basal keratinocytes and melanocytes [ 209 , 210 ].…”

Section: Plks and Tumor Developmentmentioning

confidence: 99%

“…This pathway is supposed having a tumor-promoting function in several cancers. In addition, PLK4 induces epithelial-mesenchymal transition (for reviews see [ 11 , 89 ], which is one of the key processes in aggressive tumorigenesis as depicted for oncogenic function of overexpressed PLK1 (see above). Cancer cell motility and invasiveness imply dynamic cytoskeletal re-organization and junctional cell-cell as well as cell-matrix (re)modelling [ 161 , 162 ].…”

Section: Plks and Tumor Developmentmentioning

confidence: 99%

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Modelling the Functions of Polo-Like Kinases in Mice and Their Applications as Cancer Targets with a Special Focus on Ovarian Cancer

Kressin

Fietz

Becker

et al. 2021

Cells

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Polo-like kinases (PLKs) belong to a five-membered family of highly conserved serine/threonine kinases (PLK1-5) that play differentiated and essential roles as key mitotic kinases and cell cycle regulators and with this in proliferation and cellular growth. Besides, evidence is accumulating for complex and vital non-mitotic functions of PLKs. Dysregulation of PLKs is widely associated with tumorigenesis and by this, PLKs have gained increasing significance as attractive targets in cancer with diagnostic, prognostic and therapeutic potential. PLK1 has proved to have strong clinical relevance as it was found to be over-expressed in different cancer types and linked to poor patient prognosis. Targeting the diverse functions of PLKs (tumor suppressor, oncogenic) are currently at the center of numerous investigations in particular with the inhibition of PLK1 and PLK4, respectively in multiple cancer trials. Functions of PLKs and the effects of their inhibition have been extensively studied in cancer cell culture models but information is rare on how these drugs affect benign tissues and organs. As a step further towards clinical application as cancer targets, mouse models therefore play a central role. Modelling PLK function in animal models, e.g., by gene disruption or by treatment with small molecule PLK inhibitors offers promising possibilities to unveil the biological significance of PLKs in cancer maintenance and progression and give important information on PLKs’ applicability as cancer targets. In this review we aim at summarizing the approaches of modelling PLK function in mice so far with a special glimpse on the significance of PLKs in ovarian cancer and of orthotopic cancer models used in this fatal malignancy.

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Section: Polo-like Kinases and Their Physiological Functionsmentioning

confidence: 99%

Section: Polo-like Kinases and Their Physiological Functionsmentioning

confidence: 99%

Section: Plks and Tumor Developmentmentioning

confidence: 99%

Section: Plks and Tumor Developmentmentioning

confidence: 99%

Section: Plks and Tumor Developmentmentioning

confidence: 99%

See 3 more Smart Citations

Modelling the Functions of Polo-Like Kinases in Mice and Their Applications as Cancer Targets with a Special Focus on Ovarian Cancer

Kressin

Fietz

Becker

et al. 2021

Cells

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Design, synthesis, and biological evaluation of a potent PLK4 inhibitor WY29 with 1H‐pyrazolo[3,4‐d]pyrimidine scaffold

Wang

Sun

Wang

et al. 2022

Archiv der Pharmazie

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Centriole duplication occurs once per cell cycle and is regulated by Polo‐like kinase 4 (PLK4). Overexpression of PLK4 in somatic cells can lead to the excessive formation of centrioles, directly causing chromosome segregation errors and tumorigenesis. In this study, we described our efforts to develop a series of PLK4 inhibitors with 1H‐pyrazolo[3,4‐d]pyrimidine core, and further structure‐ and receptor‐based design and optimization resulted in a potent inhibitor WY29 (IC50 = 0.027 μM), which exhibited good selectivity to other PLK family members (PLK1‐3). At the cellular level, compound WY29 showed excellent antiproliferative activity against three breast cancer cell lines (MCF‐7, BT474, and MDA‐MB‐231) while weak inhibitory activity was found on normal cell line HUVECs. In addition, the in vitro preliminary drug‐like properties evaluation of compound WY29 showed outstanding stability in human plasma and liver microsomes, and weak inhibitory activity against the major subtypes of human cytochrome P450. Also, the drug‐like properties prediction of compound WY29 displayed remarkable drug‐like properties (drug‐likeness mode score: 1.06). In conclusion, these results support the further development of compound WY29 as a lead compound for PLK4‐targeted anticancer drug discovery.

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Seize the engine: Emerging cell cycle targets in breast cancer

Fuentes‐Antrás,

Bedard,

Cescon

2024

Clinical & Translational Med

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Breast cancer arises from a series of molecular alterations that disrupt cell cycle checkpoints, leading to aberrant cell proliferation and genomic instability. Targeted pharmacological inhibition of cell cycle regulators has long been considered a promising anti‐cancer strategy. Initial attempts to drug critical cell cycle drivers were hampered by poor selectivity, modest efficacy and haematological toxicity. Advances in our understanding of the molecular basis of cell cycle disruption and the mechanisms of resistance to CDK4/6 inhibitors have reignited interest in blocking specific components of the cell cycle machinery, such as CDK2, CDK4, CDK7, PLK4, WEE1, PKMYT1, AURKA and TTK. These targets play critical roles in regulating quiescence, DNA replication and chromosome segregation. Extensive preclinical data support their potential to overcome CDK4/6 inhibitor resistance, induce synthetic lethality or sensitise tumours to immune checkpoint inhibitors. This review provides a biological and drug development perspective on emerging cell cycle targets and novel inhibitors, many of which exhibit favourable safety profiles and promising activity in clinical trials.

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Polo-Like Kinase 4’s Critical Role in Cancer Development and Strategies for Plk4-Targeted Therapy

Cited by 38 publications

References 238 publications

Modelling the Functions of Polo-Like Kinases in Mice and Their Applications as Cancer Targets with a Special Focus on Ovarian Cancer

Modelling the Functions of Polo-Like Kinases in Mice and Their Applications as Cancer Targets with a Special Focus on Ovarian Cancer

Design, synthesis, and biological evaluation of a potent PLK4 inhibitor WY29 with 1H‐pyrazolo[3,4‐d]pyrimidine scaffold

Seize the engine: Emerging cell cycle targets in breast cancer

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