ARID1A 基因突变在胃癌精准治疗中的分子机制及应用研究

Gastric cancer is often diagnosed at advanced stages, and there are no effective therapies for patients with advanced gastric cancer. Thus, although the incidence of gastric cancer is not high, gastric cancer is the second leading cause of cancer deaths worldwide, and the death rate for gastric cancer is similar to that for lung cancer. It is critical to identify key genetic alterations in gastric cancer to permit development of novel effective targeted therapy for this disease. Notably, recent genomic sequencing studies have shown that the ARID1A gene (AT-rich interactive domain 1A, also known as BAF250a) is mutated in more than 20% of gastric cancers and in more than 87% of gastric cancers with genomic instability.. ARID1A is a subunit of the SWI/SNF chromatin remodeling complex, which uses the energy of ATP hydrolysis to remodel chromatin structure. Our most recent study showed that ARID1A functions as a key epigenetic regulator of DNA damage checkpoint machinery to sustain DNA damage signaling and facilitate DNA repair. Since an intact DNA damage response is essential for preventing genomic instability and cancer development, this novel function of ARID1A may explain how ARID1A aberrations contribute to the development of gastric cancer. More importantly, we found that ARID1A-deficient cancer cells were sensitive to the DNA-damaging agents PARP (poly[ADP-ribose] polymerase) inhibitors.. On the basis of these results, we hypothesize that ARID1A suppresses the development of gastric cancer by preserving genomic stability and that targeting defective DNA damage response and repair constitutes an effective targeted therapy for ARID1A-deficient gastric cancer. We will test this hypothesis by pursuing three specific aims: (1) Determine the function of ARID1A as a novel epigenetic regulator of genomic stability. (2) Determine the functional significance of ARID1A mutations found in gastric cancer patient specimens. In aims 1 and 2, we will use biochemistry approaches and the cutting-edge CRISPR/Cas9 technology to systematically study the molecular mechanisms for ARID1A function in genome maintenance and the functional significance of patient-derived ARID1A mutations. (3) Target ARID1A-deficient gastric cancer via synthetic lethality approaches. We will test whether PARP inhibitors and DNA damage checkpoint inhibitors can selectively kill ARID1A-deficient gastric cancer cells by targeting defective DNA damage response.. If successful, our study will not only reveal novel key pathologic insights into how ARID1A deficiency contributes to gastric cancer development but also facilitate development of novel targeted and/or combination therapies for ARID1A-deficient gastric cancer and identify, on the basis of ARID1A mutation status, which gastric cancer patients are most likely to benefit from those therapies.

胃癌是我国常见恶性肿瘤，发病和死亡率高，除手术和放化疗外，尚缺乏有效低毒的分子靶向治疗药物可以提高胃癌治疗疗效。研究表明，超过20%的胃癌存在ARID1A基因突变。由于DNA损伤应答是保证基因组稳定性和防止肿瘤发生的重要机制，且本研究组前期研究揭示：ARID1A是调控DNA损伤应答的关键分子，因此我们提出研究假设：对于ARID1A缺陷型胃癌，采用针对DNA损伤应答的靶向治疗可能有效。我们将从三个方面验证这一假说：(1)进一步证明ARID1A是维持基因组稳定性的关键调控因子；（2）分析胃癌ARID1A基因突变的功能和作用；（3）通过体内外实验检测PARP抑制剂和DNA损伤修复抑制剂对ARID1A缺陷型胃癌的协同致死效应。本课题将对ARID1A缺失参与胃癌发生和发展的机制进行深入研究，并希冀找到治疗ARID1A缺陷型胃癌新的靶向药物，有望给胃癌患者带来新的治疗契机。

胃癌是我国常见恶性肿瘤，发病和死亡率高，除手术和放化疗外，尚缺乏有效低毒的分子靶向治疗药物可以提高胃癌治疗疗效。研究表明，超过20%的胃癌存在ARID1A基因突变。本研究发现：1）p-AKT在ARID1A缺陷型胃癌组织中高表达，并且在p-AKT高表达的细胞中，AKT抑制剂可增强PARP抑制剂的抑制作用。在P53突变型胃癌细胞中，敲低ARID1A可上调p-AKT的表达，AKT抑制剂可增强PARP抑制剂的促细胞凋亡作用。2）通过对年轻胃癌患者肿瘤进行靶向ARID1A 基因测序，首次揭示了早发胃癌患者中ARID1A 基因的遗传改变和蛋白表达模式。相较于ARID1A 野生型胃癌患者，ARID1A 突变（包括编码区突变和非编码区突变）患者生存时间更长。通过对肿瘤微环境进行空间分析，首次揭示了肿瘤及其癌旁组织中的ARID1A 表达模式对其用作肿瘤发生、肿瘤免疫应答和临床预后的潜在预测性标志物具有重大临床意义。