在多种恶性肿瘤中，高度活化的Ras因能够调控多条致癌通路，一直被认为是抗癌的重要靶点。Ras活化诱导肿瘤细胞通过巨胞饮作用大量摄取细胞外可溶性蛋白质作为氨基酸来源，以维持营养应激时的生存和增殖。我们在前期研究中发现了一种熊果酸衍生物——UA17，可以通过过度活化巨胞饮来诱导细胞发生一种新型非凋亡的死亡模式——巨泡式死亡。在本项目中，我们在KRAS突变型肺癌中对UA17对巨胞饮和巨泡式死亡的诱导能力进行进一步验证，同时解析其与Ras信号通路的相关性及分子调控机制。利用这一独特的內吞途径，我们提出了一种诱导肿瘤细胞“吃药”的全新的药物联用组合，并拟在体内体外的肿瘤模型中对其抗癌作用进行验证。针对UA17的巨胞饮诱导活性及将其与化疗药物联用的研究，不仅可以为巨胞饮诱导剂的研发与应用奠定坚实的理论基础，更为Ras靶向的肿瘤治疗提供了一种全新的药物联用模式。

Hyperactivated Ras regulates many oncogenic pathways in several malignant human cancers and it is an attractive target for cancer therapies. Ras activation in cancer cells drives protein internalization via macropinocytosis as a key nutrient-gaining process. In our previous work, we found that an ursolic acid derived small molecule (UA17) could induce methuosis which is a novel non-apoptotic cell death through hyperstimulation of macropinocytosis. In this study, we will verify the inducibility of UA17 on macropinocytosis and methuosis in KRAS mutant lung cancer cells and the molecular mechanism of macropinocytosis induced by UA17 and the correlation with Ras signaling pathway. By utilizing this unique endocytosis pathway, here we create a drug combination that can induce cancer cells to ‘drink drugs’. The anti-cancer effect will be proven by in vitro and in xenograft tumour models. This strategy of targeting the macropinocytosis caused by UA17 will provide a solid theoretical support and effective pre-research base for the development of macropinocytosis inducer and a novel drug combination in precision therapy of RAS-activated cancers.