PARP抑制剂SC10914在胃癌中的抗肿瘤作用及机制探索

Antitumor effect and potential mechanism of PARP inhibitor SC10914 in gastric cancer

目的探索新型PARP抑制剂SC10914在胃癌中的作用和潜在机制。方法体外胃癌细胞系(HGC-27、MGC803、MKN45、NCI-N87及SNU-1)经不同浓度的SC10914处理后,细胞计数试剂盒检测细胞增殖活性,流式细胞仪和免疫印迹法检测SC10914对细胞周期和上皮间质转化的影响。选取5例人源化胃癌移植瘤(patient-derived xenograft,PDX)模型评估SC10914单药及联合紫杉醇的抗肿瘤作用。靶向捕获测序分析细胞系及胃癌PDX组织中BRCA1、BRCA2及ATM等基因的变异。结果 SC10914对胃癌细胞系具有选择性抗增殖作用。HGC-27(ATM基因突变同时ATM蛋白低表达)和MGC803细胞(携带BRCA1/2基因突变)对SC10914的敏感性高于其他3株细胞。SC10914可诱导胃癌细胞发生G2/M期阻滞,并抑制细胞发生上皮间质转化。SC10914在5例胃癌PDX模型中抑瘤率为30.1%～58.4%;且SC10914联合紫杉醇仅在2例模型中显示出一定的协同抑瘤作用。结论 SC10914在胃癌中显示出一定的抗肿瘤作用,但其明确的疗效预测标志物尚有待深入挖掘。

Objective To investigate the antitumor activity and underlying mechanisms of a novel PARP inhibitor(SC10914) in gastric cancer(GC).Method Human GC cell lines(HGC-27、MGC803、MKN45、NCI-N87 and SNU-1) were treated with SC10914 at different concentrations,and the cell proliferation activity was detected by CCK-8 method.The effect of SC10914 on cell cycle and epithelial-mesenchymal transition were detected by flow cytometry and immunoblot.For in vivo studies,five patientderived xenografts(PDXs) were selected to evaluate the antitumor activity of SC10914 monotherapy and combined with Paclitaxel.Targeted capture sequencing was used to detect the mutations of BRCA1,BRCA2 and ATM in cell lines and GC PDXs.ResultSC10914 had a selective anti-proliferative effect on GC cell lines.HGC-27(with ATM mutation and low ATM expression) and MGC-803(with BRCA1/2 mutations) were more sensitive to SC10914 than the other three cell lines.Furthermore,SC10914 could induce cell cycle arrest at G2/M phase and inhibit epithelial-mesenchymal transition in GC cells.However,the tumor growth inhibition rate of SC10914 on five GC PDX models was moderate(30.1% ~ 65.0%,P < 0.001),and the synergistic effect of SC10914 and Paclitaxel was only observed on two models.Conclusion Our results showed that SC10914 had moderate antitumor effect on GC.However,the biomarker to predict response of SC10914 needed further exploration.