文章：

Polo样激酶1抑制剂在小细胞肺癌临床前模型中展现出体外与体内疗效

Polo-like Kinase 1 Inhibitors Demonstrate In Vitro and In Vivo Efficacy in Preclinical Models of Small Cell Lung Cancer

原文发布日期：28 January 2025

DOI: 10.3390/cancers17030446

类型: Article

开放获取: 是

英文摘要：

Objective:To investigate the preclinical efficacy and identify predictive biomarkers of polo-like kinase 1 (PLK1) inhibitors in small cell lung cancer (SCLC) models.Methods:We tested the cytotoxicity of selective PLK1 inhibitors (rigosertib, volasertib, and onvansertib) in a panel of SCLC cell lines. We confirmed the therapeutic efficacy of subcutaneous xenografts of representative cell lines and in four patient-derived xenograft models generated from patients with platinum-sensitive and platinum-resistant SCLC. We employed an integrated analysis of genomic and transcriptomic sequencing data to identify potential biomarkers of the activity and mechanisms of resistance in laboratory-derived resistance models.Results:Volasertib, rigosertib, and onvansertib showed strong in vitro cytotoxicity at nanomolar concentrations in human SCLC cell lines. Rigosertib, volasertib, and onvansertib showed equivalent efficacy to that of standard care agents (irinotecan and cisplatin) in vivo with significant growth inhibition superior to cisplatin in PDX models of platinum-sensitive and platinum-resistant SCLC. There was an association betweenYAP1expression and disruptive or inactivationTP53gene mutations, with greater efficacy of PLK1 inhibitors. Comparison of lab-derived onvansertib-resistant H526 cells to parental cells revealed differential gene expression with upregulation ofNAP1L3,CYP7B1,AKAP7, andFOXG1and downregulation ofRPS4Y1,KDM5D,USP9Y, andEIF1AYhighlighting the potential mechanisms of resistance in the clinical setting.Conclusions:We established the efficacy of PLK1 inhibitors in vitro and in vivo using PDX models of platinum-sensitive and resistant relapsed SCLC. An ongoing phase II trial is currently testing the efficacy of onvansertib in patients with SCLC (NCT05450965).

摘要翻译： 

目的：探讨Polo样激酶1（PLK1）抑制剂在小细胞肺癌（SCLC）模型中的临床前疗效并确定其预测性生物标志物。 方法：我们在多株SCLC细胞系中测试了选择性PLK1抑制剂（rigosertib、volasertib和onvansertib）的细胞毒性。通过代表性细胞系的皮下移植瘤模型，以及源自铂类敏感与铂类耐药SCLC患者的四例患者来源异种移植模型，验证了其治疗效果。我们整合分析了基因组与转录组测序数据，以识别实验室构建的耐药模型中药物活性及耐药机制的潜在生物标志物。 结果：Volasertib、rigosertib和onvansertib在纳摩尔浓度下对人SCLC细胞系展现出强烈的体外细胞毒性。在体内实验中，rigosertib、volasertib和onvansertib的疗效与标准治疗药物（伊立替康和顺铂）相当，且在铂类敏感与铂类耐药SCLC的PDX模型中，其生长抑制作用显著优于顺铂。YAP1表达与TP53基因破坏性或失活性突变之间存在关联，且与PLK1抑制剂疗效增强相关。实验室构建的onvansertib耐药H526细胞与亲本细胞的比较显示，NAP1L3、CYP7B1、AKAP7和FOXG1基因表达上调，而RPS4Y1、KDM5D、USP9Y和EIF1AY表达下调，这揭示了临床环境中潜在的耐药机制。 结论：我们通过铂类敏感及耐药复发SCLC的PDX模型，证实了PLK1抑制剂在体外和体内的疗效。一项正在进行的II期临床试验正在评估onvansertib对SCLC患者的疗效（试验注册号：NCT05450965）。

原文链接：

Polo-like Kinase 1 Inhibitors Demonstrate In Vitro and In Vivo Efficacy in Preclinical Models of Small Cell Lung Cancer