CDK1 inhibition sensitizes normal cells to DNA damage in a cell cycle dependent manner

Prevo, Remko; Pirovano, Giacomo; Puliyadi, Rathi; Herbert, Katharine; Rodríguez-Berriguete, Gonzalo; O’Docherty, Alice; Greaves, W. M. H.; McKenna, W. Gillies; Higgins, Geoff S.

doi:10.1080/15384101.2018.1491236

Cited by 57 publications

(52 citation statements)

References 19 publications

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“…CDK1 is a prototype kinase, a central regulator that drives cells through G2 phase and mitosis 36 . CDK1 orchestrates the transition from the G2 phase into mitosis, and as cancer cells often display enhanced CDK1 activity, it has been proposed as a tumor-specific anti-cancer target 37 . Data mining from different databases demonstrated CDK1 upregulation in LUAD.…”

Section: Discussionmentioning

confidence: 99%

Independent prognostic implications of RRM2 in lung adenocarcinoma

Luo

Cao

et al. 2020

J. Cancer

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Background: Ribonucleoside-diphosphate reductase subunit M2 ( RRM2 ) is the catalytic subunit of ribonucleotide reductase and modulates the enzymatic activity, which is essential for DNA replication and repair. However, the role of RRM2 in lung adenocarcinoma (LUAD) remains unclear. Methods: In this study, we explored the expression pattern and prognostic value of RRM2 in LUAD across TCGA, GEO, Oncomine, UALCAN, PrognoScan, and Kaplan-Meier Plotter, and confirmed its independent prognostic value via Cox analyses. LinkedOmics and GEPIA2 were applied to investigate co-expression and functional networks associated with RRM2 . Besides, we used TIMER to assess the correlation between RRM2 and the main six types of tumor-infiltrating immune cells. Lastly, the correlations between immune signatures of immunomodulators, chemokines, and 28 tumor-infiltrating lymphocytes (TILs) and RRM2 were examined by tumor purity-corrected partial Spearman's rank correlation coefficient through TIMER portal. Results: RRM2 was found upregulated in tumor tissues in TCGA-LUAD, and validated in multiple independent cohorts. Moreover, whether in TCGA or other cohorts, high RRM2 expression was found to be associated with poor survival. Cox analyses showed that high RRM2 expression was an independent risk factor for overall survival, disease-specific survival, and progression-free survival of LUAD. Functional network analysis suggested that RRM2 regulates RNA transport, oocyte meiosis, spliceosome, ribosome biogenesis in eukaryotes, and cellular senescence signaling through pathways involving multiple cancer-related kinases and E2F family. Also, RRM2 expression correlated with infiltrating levels of B cells, CD4+ T cells, and neutrophils. Subsequent analysis found that B cells and dendritic cells could predict the outcome of LUAD. B cells were identified as an independent risk factor among six types of immune cells through Cox analyses. At last, the correlation analysis showed RRM2 correlated with 67.68% (624/922) of the immune signatures we performed. Conclusion: Our research showed that RRM2 could independently predict the prognosis of LUAD and was associated with immune infiltration. In particular, the tight relationship between RRM2 and B cell marker genes are the potential epicenter of the immune response and one of the critical factors affecting the prognosis. Our findings laid the foundation for further research on the immunomodulatory role of RRM2 in LUAD.

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Section: Discussionmentioning

confidence: 99%

Independent prognostic implications of RRM2 in lung adenocarcinoma

Luo

Cao

et al. 2020

J. Cancer

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“…24 – 26 CDK1 -encoding proteins drive the cell cycle by phosphorylation of Ser/Thr proteins. 27 The potential mechanism enhances the radiosensitivity of cancer cells related to homologous recombination repair 28 and genomic stability. 29 In different cancer types, AURKA drives radiosensitization from chromosomal missegregation on tripolar mitotic spindles.…”

Section: Discussionmentioning

confidence: 99%

<p>Prognostic Values of Radiosensitivity Genes and CD19 Status in Gastric Cancer: A Retrospective Study Using TCGA Database</p>

Liu

Huang

et al. 2020

PGPM

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Background The correlation between the radiosensitivity genes combined with CD19 status and clinical outcome was investigated to identify gastric cancer (GC) patients who would benefit from radiotherapy combined with CAR-T cell therapy. Methods The gene expression and clinical features were downloaded from The Cancer Genome Atlas (TCGA) Stomach Cancer (STAD). To identify the hub radiosensitivity genes and CD19 status, 407 patients were categorized into two groups: radiosensitivity (RS) and radioresistance (RR) based on the prognosis. The chi-square test, Mann–Whitney test, and Kaplan–Meier survival analysis were applied to compare the differential expression in these groups and analyze the correlation between the gene expression and clinical outcome and features. Finally, the influencing factors for the prognosis of GC were investigated by multiple Cox regression, especially in RS patients. Results A total of 15 differential expression genes, containing two communities with 8 hub radiosensitivity genes, were identified. We also identified a 2-gene signature model with a negative coefficient and calculated the risk score for the prognosis of GC. Also, Helicobacter pylori infection was validated, and the high-risk score of radiosensitivity genes was the risk factor, and high CD19 expression was the protective factor for the prognosis. Conclusion The radiosensitivity gene signature and CD19 expression predicted the clinical outcome of GC patients.

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“…For example, the use of Dinaciclib ((S)-3-(((3-Ethyl-5-(2-(2-hydroxyethyl)piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7-yl) amino)methyl)pyridine 1-oxide; MK-7965), which inhibits CDK1, 2, 5, and 9, has been attempted in patients with leukopenia and thrombocytopenia (Kumar et al, 2015;Mitri et al, 2015). The clinical development of AZD5438 (4-[2-Methyl-1-(1-methylethyl)-1H-imidazol-5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidinamine), which inhibits CDK1, 2, and 9, was discontinued partially because of its low tolerability and high variability in patients (Boss et al, 2010;Prevo et al, 2018). Targeted individual CDK inhibitors could protect normal cells against some cancers, but might have therapeutic value against restricted tumors showing the expression and activation of theses specific CDKs.…”

Section: Radiosensitizing Effect Of Novel Phenylpyrimidine Compoundmentioning

confidence: 99%

Radiosensitizing Effect of Novel Phenylpyrimidine Derivatives on Human Lung Cancer Cells via Cell Cycle Perturbation

Jung¹,

Nam²,

Park³

et al. 2019

J Pharmacol Exp Ther

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Radiotherapy is one of the most common treatments for cancer, but radioresistance and injury to normal tissue are considered major obstacles to successful radiotherapy. Thus, there is an urgent need to develop radiosensitizers to improve the therapeutic outcomes of radiotherapy in cancer patients. Our previous efforts to identify novel radiosensitizers, using high-throughput screening targeting p53 and Nrf2 revealed a promising N-phenylpyrimidin-2-amine (PPA) lead compound. In the present study, 17 derivatives of this lead compound were examined, and it was found that 4-(4-fluorophenyl)-N-(4-nitrophenyl)-6-phenylpyrimidin-2-amine (PPA5), 4-((4-(4fluorophenyl)pyrimidin-2-yl)amino)-3-methoxy-N-methyl-benzamide (PPA13), 4-((4-(4-fluorophenyl)pyrimidin-2-yl)amino)benzenesulfonamide (PPA14), 4-((4-(2-chlorophenyl)pyrimidin-2-yl) amino)benzenesulfonamide (PPA15), and 4-((4-(2-chlorophenyl) pyrimidin-2-yl)amino)-N-methylbenzamide (PPA17) inhibited cell viability by more than 50%, with a marked increase in the proportion of cells arrested at the G 2 /M phase of cell cycle. Among these compounds, PPA15 markedly increased the sub-G 1 cell population and increased the levels of cyclin B1 and the phosphorylation levels of cyclin-dependent kinase (CDK) 1. Combined treatment with radiation and PPA14 or PPA15 significantly decreased clonogenic survival. An in vitro kinase assay revealed that PPA15 inhibited multiple CDKs involved in cell cycle regulation. Compared with drug or radiation treatment alone, combined treatment with PPA15 and radiation resulted in the suppression of A549 tumor growth in mice by 59.5% and 52.7%, respectively. Treatment with PPA15 alone directly inhibited tumor growth by 25.7%. These findings suggest that the novel pan CDK inhibitor, PPA15, may be a promising treatment to improve the effectiveness of radiotherapy for the treatment of cancer. SIGNIFICANCE STATEMENT Several inhibitors of CDK have been successfully evaluated in combination with other chemotherapeutics in clinical trials, but negative side effects have partially restricted their clinical use. In this study, we identified a novel pan-CDK inhibitor to increase radiosensitivity, and we hope this work will encourage the development of promising small-molecule radiosensitizers.

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CDK1 inhibition sensitizes normal cells to DNA damage in a cell cycle dependent manner

Cited by 57 publications

References 19 publications

Independent prognostic implications of RRM2 in lung adenocarcinoma

Independent prognostic implications of RRM2 in lung adenocarcinoma

<p>Prognostic Values of Radiosensitivity Genes and CD19 Status in Gastric Cancer: A Retrospective Study Using TCGA Database</p>

Radiosensitizing Effect of Novel Phenylpyrimidine Derivatives on Human Lung Cancer Cells via Cell Cycle Perturbation

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