Abstract：
Pancreatic cancer is one of the most lethal cancer types with 5-year survival rate of ∼10.8%. Various KRAS mutations exist in ∼85% pancreatic cancer cell lines. Mutated KRAS is a major cause that leads cancer cell proliferation. Chemotherapy is still the major treatment for pancreatic cancer. Alternatively, repositioning old drug to inhibit mutated KRAS may be a cost-effective way for pancreatic cancer treatment. In this study, we choose mutated KRAS (G12D) as a target. Based on mutated KRAS GTP binding domain (hydrolyze GTP to GDP), we perform virtual screening on FDA-approved drugs. Montelukast shows strong binding affinity to mutated KRAS as well as interfering both GTP and GDP binding to mutated KRAS. Furthermore, Montelukast shows very strong anti-proliferation effect on mutated KRAS pancreatic cancer cells both in vitro and in vivo. Our results support repositioning of Montelukast as single agent for pancreatic cancer treatment.
摘要：
胰腺癌是最致命的癌症类型之一，5年生存率为10.8%。各种KRAS突变存在于85%的胰腺癌细胞系中。突变的KRAS是导致癌细胞增殖的主要原因。化疗仍然是胰腺癌的主要治疗方法。或者，重新定位旧药物以抑制突变的KRAS可能是一种经济有效的胰腺癌治疗方法。在这项研究中,我们选择突变的KRAS(G12D)作为靶标。基于突变的KRASGTP结合域（将GTP水解为GDP），我们对FDA批准的药物进行虚拟筛选。孟鲁司特显示出对突变的KRAS的强结合亲和力以及干扰GTP和GDP与突变的KRAS的结合。此外，孟鲁司特在体外和体内对突变的KRAS胰腺癌细胞显示出非常强的抗增殖作用。我们的结果支持孟鲁司特作为胰腺癌治疗的单一药物的重新定位。
