EZH2抑制剂靶向ARID1A缺陷型肝细胞癌的作用及其机理

Hepatocellular carcinoma (HCC) is treatment-refractory cancer with a dismal outcome. Limited success in the clinical management and targeted-therapy has made HCC one of the most lethal malignancies. Understanding the driver gene mutation of HCC and developing new therapeutic targets are of great important to achieve better outcome. In our previous study, the overexpression of EZH2 plays a critical role in the metastasis and progress of HCC. Previous study found that inhibition of EZH2 induced apoptosis in ARID1A-mutated HCC cells. Recently, our preliminary data demonstrated that the knocking-out of ARID1A activates histone-lysine N-methyltransferase enzyme EZH2 and p38/MK2 pathway, sensitizes HCC cells to EZH2 inhibitor, and increased the DNA damage. Moreover, we found that EZH2 inhibitor could inhibit the grow of ARID1A HCC cells synergy with MK2 inhibitor. Based on these findings, we propose the hypothesis that EZH2 inhibitor combining with MK2 inhibitors inhibits the DNA repair of ARID1A-deficient HCC cells, promotes anti-tumor effect and is a synthetic lethality for this HHC subtype. In this study, we aim to elucidate the role and mechanism of EZH2 inhibitor combining with MK2 inhibitor in inhibiting the growth of ARID1A-deficient HCC. Collectively, the findings of this study would provide insights into the optimum strategy for using EZH2 and MK2 inhibitor as targeted-therapy for ARID1A HCC and thus providing the rationale for potential clinical application.

肝细胞癌(HCC)恶性度高，预后差，化疗与靶向治疗效果非常有限。开发针对不同基因型HCC的靶向治疗是当前的研究重点。前期我们发现： EZH2在HCC高表达，在肿瘤转移和恶性进展中发挥重要作用。文献报道在携带ARID1A突变的肝癌细胞中抑制甲基转移酶EZH2能够诱导细胞凋亡。最近，我们预实验发现：敲除 ARID1A后HCC细胞EZH2活性增强与p38/MK2通路激活、对EZH2抑制剂敏感性明显增强，而DNA损伤显著增加; EZH2抑制剂与MK2抑制剂能够协同抑制ARID1A敲除肝癌细胞生长。因此，我们提出“EZH2抑制剂与MK2抑制剂通过‘合成性致死’抑制ARID1A缺陷型肝癌细胞DNA修复促进抗肿瘤的作用及机制”的假说。本项目拟采用一系列体内外实验，阐明EZH2抑制剂联合MK2抑制剂协同抑制ARID1A缺陷型HCC 的作用机制，为基于驱动基因突变的肝细胞癌精准医学提供有益的科学依据。

肝细胞癌(HCC)恶性度高，预后差，化疗与靶向治疗效果不理想。开发针对不同基因型HCC的靶向治疗是当前的研究重点。我们研究证实：（1）ARID1A是一种肿瘤抑制因子，在HCC组织低表达，ARID1A低表达与肿瘤恶性表型及预后差相关；ARID1A缺陷促进肝癌细胞增殖及侵袭迁移，从而促进肝癌恶性进展；（2）DNA遗传毒性小分子药物库筛选鉴定顺铂、伦伐替尼及APY29可靶向杀伤ARID1A缺陷型肝癌细胞；（3）顺铂可诱导ARID1A缺陷型肝癌细胞同源重组修复通路缺陷，非同源末端连接修复途径过度激活，发生DNA损伤累积，最终引起细胞凋亡。研究阐明了顺铂通过抑制ARID1A缺陷型肝癌细胞DNA修复产生合成致死效应的分子机理，获得了顺铂、伦伐替尼及APY29靶向治疗ARID1A型肝细胞癌的可靠证据，为基于驱动基因突变的肝细胞癌精准医学提供有益的科学依据。