Gastric cancer is the fifth most common malignancy and the third leading cause of cancer‐related death worldwide. Activation of c‐MET increases tumour cell survival through the initiation of the DNA damage repair pathway. PARP is an essential key in the DNA damage repair pathway. The primary role of PARP is to detect and initiate an immediate cellular response to single‐strand DNA breaks. Tumours suppressor genes such as BRCA1/2 are closely associated with the DNA repair pathway. In BRCA1/2 mutations or deficiency status, cells are more likely to develop additional genetic alterations and chromosomal instability and can lead to cancer. In this study, we investigate the role of c‐MET and PARP inhibition in a gastric cancer model. We exploited functional in vitro and in vivo experiments to assess the antitumour potential of co‐inhibition of c‐MET (SU11274) and PARP (NU1025). This leads to a reduction of gastric cancer cells viability, especially after knockdown of BRCA1/2 through apoptosis and induction of γ‐Η2ΑΧ. Moreover, in AGS xenograft models, the combinatorial treatment of NU1025 plus SU11274 reduced tumour growth and triggers apoptosis. Collectively, our data may represent a new therapeutic approach for GC thought co‐inhibition of c‐MET and PARP, especially for patients with BRCA1/2 deficiency tumours.

中文翻译：

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抑制c-MET可以增加PARP抑制剂在胃癌模型中的抗肿瘤活性。

胃癌是全球第五大最常见的恶性肿瘤和第三大癌症相关死亡原因。c-MET的激活通过启动DNA损伤修复途径来增加肿瘤细胞的存活率。PARP是DNA损伤修复途径中的关键。PARP的主要作用是检测并启动对单链DNA断裂的即时细胞反应。肿瘤抑制基因如BRCA1 / 2与DNA修复途径密切相关。在BRCA1 / 2突变或缺乏状态下，细胞更可能发生其他遗传改变和染色体不稳定，并可能导致癌症。在这项研究中，我们研究了c-MET和PARP抑制在胃癌模型中的作用。我们利用功能性的体外和体内实验评估了c-MET（SU11274）和PARP（NU1025）共同抑制的抗肿瘤潜力。这导致胃癌细胞的活力降低，尤其是在通过凋亡和γ-Η2ΑΧ诱导敲低BRCA1 / 2后。此外，在AGS异种移植模型中，NU1025加SU11274的组合治疗可减少肿瘤生长并触发细胞凋亡。总的来说，我们的数据可能代表了一种针对c-MET和PARP共同抑制GC的新治疗方法，特别是对于BRCA1 / 2缺乏肿瘤的患者。NU1025加SU11274的组合治疗可减少肿瘤生长并触发细胞凋亡。总的来说，我们的数据可能代表了一种针对c-MET和PARP共同抑制GC的新治疗方法，特别是对于BRCA1 / 2缺乏肿瘤的患者。NU1025加SU11274的组合治疗可减少肿瘤生长并触发细胞凋亡。总的来说，我们的数据可能代表了一种针对c-MET和PARP共同抑制GC的新治疗方法，特别是对于BRCA1 / 2缺乏肿瘤的患者。