ARID1A是SWI/SNF染色体重构复合体的一部分。作为一个肿瘤抑制基因，多种肿瘤中伴随着该基因的失活突变。鉴于该基因的高突变率，开发针对该基因的靶向药物是近年来研究的热点。本研究中，申请人拟采用协同致死的策略开发基于ARID1A的靶向药物。申请人前期研究中通过基因敲除和过表达构建了ARID1A等基因细胞系，并对表观遗传药物库进行了筛选，发现Aurora A激酶抑制剂与ARID1A之间存在协同致死效应。为了进一步挖掘ARID1A相关的协同致死因子，本课题拟对miRNA文库进行筛选，并通过转录组测序、结直肠癌细胞模型、动物模型及结直肠癌组织样本，探究结肠癌中与ARID1A具有协同致死效应的基因及信号通路，并阐明其协同作用的分子机制。本研究不仅有助于加深对结直肠癌细胞中分子调控网络的认识，同时为结直肠癌的治疗提供新思路。

ARID1A, a component of the SWI/SNF chromatin remodeling complex, is a tumor suppressor with a high frequency of inactivating mutations in many cancers. Therefore, ARID1A deficiency has been exploited therapeutically for treating cancer. Here we plan to develop anti-cancer drugs with a synthetic lethality approach. Through Epigenetic drug library screening in ARID1A knockout and overexpression cells, we previously demonstrated that targeting AURKA-CDC25C axis could induce synthetic lethality in ARID1A deficient cells. In order to dig more potential ARID1A related synthetic lethal partners, we plan to screen miRNA library. Here we will use multiple approaches including cell and animal models as well as human cancer tissues to identify ARID1A synthetic lethal partners in colorectal cancer cells, and elucidate underlying mechanisms. Our study would not only provide novel insight of regulation networks into colorectal cancer but also develop novel therapeutic methods targeting colorectal cancer.