OBJECTIVE: To investigate the effects of PLK1 inhibitors on Osimertinib-resistant NCI-H1975 cell lines and the anti-tumor effect combined with Osimertinib.
METHODS: Osimertinib resistant NCI-H1975 cell lines were constructed by the methods of concentration-increasing.; The classical tumor pathway inhibitor library compounds were combined with Osimertinib on Osimertinib-resistant cells to screen compounds with synergistic effects with Osimertinib; The gene set enrichment analysis (GSEA) was used to investigate the activations of signaling pathways in Osimertinib-resistant cells; Sulforhodamine B (SRB) staining was used to investigate the inhibitory effect of PLK1 inhibitors on Osimertinib-resistant cells and the anti-tumor effect of PLK1 inhibitors combined with Osimertinib.
RESULTS: Osimertinib-resistant cells lines H1975-resistance (resistance index=43.45) were successfully established. The PLK1 inhibitors BI 2536 and GSK461324 have synergistic effect with Osimertinib. Compared with Osimertinib-sensitive cells, PLK1 regulatory pathway and cell cycle pathway were significantly activated in Osimertinib-resistant cells. In a cohort of NSCLC patients with epidermal growth factor receptor mutations treated with Osimertinib, PLK1 mRNA levels were negatively correlated with progression free survival of patients (R=0.62, P<0.05), confirming that excessive activation of PLK1 in NSCLC cells may cause cell resistance to Osimertinib. Further vitro experiments showed that, The IC50 of PLK1 inhibitors BI 6727 and GSK461324 in Osimertinib-resistant cells were lower than those in sensitive ones. Compared to the mono treatment of Osimertinib, PLK1 inhibitors combined with Osimertinib behave significantly stronger effect on the proliferation of Osimertinib-resistant cells.
CONCLUSIONS: PLK1 inhibitors combined with Osimertinib behave stronger anti-tumor effect to Osimertinib-resistant NSCLC cells and may be used for intervention and treatment of Osimertinib resistance.
目的: 研究Polo样激酶1（PLK1）抑制剂在奥希替尼耐药的非小细胞肺癌（NSCLC）NCI-H1975细胞中的作用效果及其合用奥希替尼的抗肿瘤效果。方法: 利用药物浓度递增法构建对奥希替尼耐药的H1975细胞模型；在耐药细胞上合用肿瘤经典通路抑制剂库化合物与奥希替尼，筛选与奥希替尼存在协同作用的化合物；利用基因集富集分析考察奥希替尼耐药通路；利用磺酰罗丹明B染色法考察PLK1抑制剂对奥希替尼耐药细胞的抑制作用及其合用奥希替尼的抗肿瘤作用。结果: 成功建立奥希替尼耐药细胞模型（耐药指数=43.45）。PLK1抑制剂GSK461364和BI 2536与奥希替尼存在协同作用，与敏感细胞相比，奥希替尼耐药细胞中PLK1调控通路和细胞周期通路显著激活，且在接受奥希替尼治疗的表皮生长因子受体突变NSCLC患者队列中，PLK1 信使RNA水平与患者的无进展生存期呈负相关（R=0.62，P<0.05），证实NSCLC细胞中PLK1过度激活可能导致细胞对奥希替尼耐药。进一步体外实验发现，PLK1抑制剂BI 6727和GSK461324对奥希替尼耐药细胞的半抑制浓度小于敏感细胞，相较于单用奥希替尼，PLK1抑制剂与奥希替尼合用可显著增强对耐药细胞的增殖抑制作用。结论: PLK1抑制剂与奥希替尼合用对奥希替尼耐药的NSCLC细胞的抑制作用更强，有可能用于奥希替尼耐药患者的干预和治疗。.

Polo like kinase 1 (PLK1) is a serine/threonine kinase that is widely distributed in eukaryotic cells and plays an important role in multiple phases of the cell cycle. Its importance in tumorigenesis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of novel dihydropteridone derivatives (13a-13v and 21g-21l) possessing oxadiazoles moiety as potent inhibitors of PLK1. Compound 21g exhibited improved PLK1 inhibitory capability with an IC50 value of 0.45 nM and significant anti-proliferative activities against four tumor-derived cell lines (MCF-7 IC50 = 8.64 nM, HCT-116 IC50 = 26.0 nM, MDA-MB-231 IC50 = 14.8 nM and MV4-11 IC50 = 47.4 nM) with better pharmacokinetic characteristics than BI2536 in mice (AUC0-t = 11 227 ng h mL-1vs 556 ng h mL-1). Moreover, 21g exhibited moderate liver microsomal stability and excellent pharmacokinetic profile (AUC0-t = 11227 ng h mL-1, oral bioavailability of 77.4%) in Balb/c mice, acceptable PPB, improved PLK1 inhibitory selectivity, and no apparent toxicity was observed in the acute toxicity assay (20 mg/kg). Further investigation showed that 21 g could arrest HCT-116 cells in G2 phase and induce apoptosis in a dose-dependent manner. These results indicate that 21g is a promising PLK1 inhibitor.

UNASSIGNED: To provide a systematic review of existing meta-analysis on the efficacy, safety and pharmacokinetics of the novel Polo-like kinase-1 (Plk1) inhibitors in various tumor treatments, and assess the methodological quality and the strength of evidence of the included meta-analysis.
UNASSIGNED: The Medline, PubMed, Embase, etc. were searched and updated on 30 June 2022. 22 eligible clinical trials involving a total of 1256 patients were included for analyses. Randomised controlled trials (RCTs) compared the efficacy or safety, or both of any Plk1 inhibitors with placebo (active or inert) in participants. To be included, studies had to be RCTs, quasi-RCTs, and nonrandomized comparative studies.
UNASSIGNED: A meta-analysis of two trials reported progression-free survival (PFS) of the overall population (effect size (ES), 1.01; 95% confidence intervals (CIs), 0.73-1.30, I2 =0.0%, P<0.001) and overall survival (OS) of the overall population (ES, 0.91; 95% CIs, 0.31-1.50, I2 =77.6%, P=0.003). 18 adverse events (AEs) reflected that the possibility of occurrence of AEs in the Plk1 inhibitors group was 1.28 times higher than in the control group (odds ratios (ORs), 1.28; 95% CIs,1.02-1.61). The results of meta-analysis showed that the incidence of AEs in the nervous system was the highest (ES, 0.202; 95% CIs, 0.161-0.244), followed by blood system (ES, 0.190; 95% CIs, 0.178-0.201) and digestive system (ES, 0.181; 95% CIs, 0.150-0.213). Rigosertib (ON 01910.Na) was associated with a decreased risk of AEs in digestive system (ES, 0.103; 95% CIs, 0.059-0.147), but BI 2536 and Volasertib (BI 6727) increased risk of AEs in blood system (ES, 0.399; 95% CIs, 0.294-0.504). Five eligible studies reported the pharmacokinetic parameters of the low dosage (100 mg) cohort and the high dosage (200 mg) cohort, and there was no statistical difference in the total plasma clearance, terminal half-life and apparent volume of distribution at steady state.
UNASSIGNED: Plk1 inhibitors work better in improving OS and they are well tolerated, effective and safe in reducing the severity of illness while improving the quality of life, especially in patients with non-specific tumors, respiratory system tumors, musculoskeletal system tumors, and urinary system tumors. However, they fail to prolong the PFS. From the vertical whole level analysis, compared to other systems in the body, Plk1 inhibitors should be avoided as far as possible for the treatment of tumors related to the blood circulatory system, digestive system and nervous system, which were attributed to the intervention of Plk1 inhibitors associated with an increased risk of AEs in these systems. The toxicity caused by immunotherapy should be carefully considered. Conversely, a horizontal comparison of three different types of Plk1 inhibitors suggested that Rigosertib (ON 01910.Na) might be relatively suitable for the treatment of tumors associated with the digestive system, while Volasertib (BI 6727) might be even less suitable for the treatment of tumors associated with the blood circulation system. Additionally, in the dose selection of Plk1 inhibitors, the low dose of 100 mg should be preferred, and meanwhile, it can also ensure the pharmacokinetic efficacy that is indistinguishable from the high dose of 200 mg.
UNASSIGNED: https://www.crd.york.ac.uk/prospero/, identifier CRD42022343507.

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