抗黑色素瘤MAPK靶向耐药的天然化合物筛选与药物作用机理研究

恶性黑色素瘤是具有高度侵袭性的恶性肿瘤，晚期无法进行手术治疗，且化疗和放疗效果十分有限。联合BRAF和MEK抑制剂的治疗方案显著提高了BRAF V600突变型黑色素瘤的响应率和生存率，但大部分患者短时间内产生获得性耐药。已有许多研究对MAPK抑制剂的多种耐药机制进行了报道，并据此开发了新型抑制剂和联合治疗方案，目前未有明显成效。近年来，众多研究证实了天然产物的抗癌活性，为新型抗癌药物的研究提供了思路。本课题通过构建BRAFi/MEKi双药耐药黑色素瘤细胞株，对天然产物库进行高通量筛选，得到有效杀伤耐药细胞的天然化合物—汉防己甲素（TET），并鉴定其作用靶点为KPNB1。作为首个发现TET克服黑色素瘤MAPK靶向耐药的研究，我们将结合体内外实验和计算机药物辅助分析，对TET的作用靶点和下游分子机理进行深入探讨。这将有利于优化TET药物结构和探索针对MAPKi耐药黑色素瘤的新兴联合治疗方案。

Malignant melanoma is a highly aggressive malignant tumor that cannot be treated with surgery at the advanced stage, and the effects of chemotherapy and radiotherapy are very limited. The combined treatment of BRAF and MEK inhibitors greatly improved the response rate and survival rate of BRAF V600 mutant melanoma, but most patients developed acquired resistance in a short time. Many studies have reported on the multiple resistance mechanisms of MAPK inhibitors, and based on this, new inhibitors and combination treatments have been developed. However, there is no obvious effect so far. In recent years, numerous studies have confirmed the anti-cancer activity of natural products, providing ideas for the research of new anti-cancer drugs. This project uses the constructed BRAFi/MEKi dual-drug resistant melanoma cell line to conduct high-throughput screening of the natural product library, and obtains a natural compound that effectively kills drug-resistant cells, which is tetrandrine (TET). Moreover, we identified KPNB1 as the target of TET. As the first study to find that TET overcomes the MAPK targeted drug resistance of melanoma , we will combine in vivo and in vitro experiments and computer-aided pharmaceutical analysis to conduct an in-depth discussion on the target of TET and the downstream molecular mechanism. This will help optimize the structure of TET drugs and explore emerging combination treatment options for MAPKi-resistant melanoma.