PLK1 inhibition-based combination therapies for cancer management

Su, Shengqin; Chhabra, Gagan; Singh, Chandra K.; Ndiaye, Mary A.; Ahmad, Nihal

doi:10.1016/j.tranon.2021.101332

Cited by 53 publications

(42 citation statements)

References 87 publications

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“…Very recent well written reviews have been published on PLK1 structure, regulation and its role in cancer development and therapy ( 6 – 9 ), and here we summarize some key features of the PLK1 protein that could help clarifying the rationale for the design of PLK1 inhibitors and their potential side effects.…”

Section: Structure and Regulation Of Plk1mentioning

confidence: 99%

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Present and Future Perspective on PLK1 Inhibition in Cancer Treatment

Chiappa

Petrella²,

Damia³

et al. 2022

Front. Oncol.

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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.

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Section: Structure and Regulation Of Plk1mentioning

confidence: 99%

“…Different inhibitors of PLK1 have been generated through high-throughput screening approaches ( 9 , 126 , 155 ). However, many of these molecules could not be further developed because they had only modest activity in preclinical models and were shown to be non-specific protein alkylators ( 160 ).…”

Section: Plk1 Inhibitorsmentioning

confidence: 99%

Present and Future Perspective on PLK1 Inhibition in Cancer Treatment

Chiappa

Petrella²,

Damia³

et al. 2022

Front. Oncol.

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“…Thus, small-molecule kinase inhibitors (KIs) that target Aurora A, PLK1, and PLK4, respectively, have attracted intense interest, leading to dozens of KIs being designed, synthesized, and tested in preclinical and clinical settings, with some even being used in clinical trials ( 44 – 46 ). However, KIs of Aurora A, PLK1, and PLK4 as monotherapies in previous clinical trials were not satisfactory; enough evidence has suggested that KIs can significantly enhance the therapeutic efficacy of several established treatment regimens, including radiotherapies, chemotherapies, targeted therapies, and immunotherapies ( 45 ). Recently, the PLK4 inhibitor, CFI-400945, has been shown to potentially improve the efficiency of PD-1 blockade in a late-stage mouse HCC model.…”

Section: Discussionmentioning

confidence: 99%

CEP192 is a novel prognostic marker and correlates with the immune microenvironment in hepatocellular carcinoma

Liang

Chang

et al. 2022

Front. Immunol.

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Hepatocellular carcinoma (HCC) responds poorly to standard chemotherapy or targeted therapy; hence, exploration for novel therapeutic targets is urgently needed. CEP192 protein is indispensable for centrosome amplification, which has been extensively characterized in both hematological malignancies and solid tumors. Here, we combined bioinformatics and experimental approaches to assess the potential of CEP192 as a prognostic and therapeutic target in HCC. CEP192 expression increased with tumor stage and was associated with poor clinicopathologic features, frequent recurrence, and higher mortality. Upon single-cell RNA sequencing, CEP192 was found to be involved in the proliferation and self-renewal of hepatic progenitor-like cells. This observation was further evidenced using CEP192 silencing, which prevented tumor cell proliferation and self-renewal by arresting cells in the G0/G1 phase of the cell cycle. Notably, CEP192 was highly correlated with multiple tumor-associated cytokine ligand–receptor axes, including IL11–IL11RA, IL6–IL6R, and IL13–IL13RA1, which could promote interactions between hepatic progenitor-like cells, PLVAP+ endothelial cells, tumor-associated macrophages, and CD4+ T cells. Consequently, CEP192 expression was closely associated with an immunosuppressive tumor microenvironment and low immunophenoscores, making it a potential predictor of response to immune checkpoint inhibitors. Taken together, our results unravel a novel onco-immunological role of CEP192 in establishing the immunosuppressive tumor microenvironment and provide a novel biomarker, as well as a potential target for therapeutic intervention of HCC.

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“…For this reason, many studies have reported the anticancer activities of PLK1 inhibitors in different cancer types. 12 . Although monotherapeutic use is promising, combination treatments have also been found to be effective in many studies 13 .…”

Section: Discussionmentioning

confidence: 99%

Investigation of the potential antitumor activity of PLK1 inhibitor SBE13 in colon cancer cell line HT29

GÖMEÇ

Yulak

Ergül

2022

CMJ

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Background: High levels of Polo-like kinase 1 (PLK1), which have been found to be abnormally expressed in many tumor types, are known to contribute to tumorigenesis and poor prognosis. Therefore, specific targeting of PLK1 is an important strategy for cancer therapy. In this study, it was aimed to investigate the cytotoxic effect of SBE13, one of the PLK1 inhibitors, against HT29 colon adenocarcinoma cells and its apoptotic potential. Methods: The cytotoxic effect of SBE13 on HT29 was determined by XTT colorimetric assay. Flow cytometry was also used to determine apoptosis. Results: SBE13 showed a dose-dependent cytotoxic effect in HT29 cells and its IC50 value was calculated as 11.79 µM for 48 h. Moreover, the Annexin V binding assay revealed that SBE13 treatment significantly increased the apoptosis in HT29 cells. Conclusion: Generally, SBE13 exerts a cytotoxic effect promoted by apoptosis in colon cancer cells HT29. Although the anticancer efficacy of SBE13 in colon cancer is promising, this potential effect should be reinforced by further studies.

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PLK1 inhibition-based combination therapies for cancer management

Cited by 53 publications

References 87 publications

Present and Future Perspective on PLK1 Inhibition in Cancer Treatment

Present and Future Perspective on PLK1 Inhibition in Cancer Treatment

CEP192 is a novel prognostic marker and correlates with the immune microenvironment in hepatocellular carcinoma

Investigation of the potential antitumor activity of PLK1 inhibitor SBE13 in colon cancer cell line HT29

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