RAF抑制剂对BRAF突变黑色素瘤的临床治疗效果受到肿瘤适应性耐药的制约。我们前期研究发现，RAF抑制剂能迅速诱导lncRNA SAMMSON表达上调，促进黑色素瘤细胞对RAF抑制剂的适应性耐受，但具体机制不明。进一步研究发现敲低SAMMSON能显著上调p53蛋白表达，激活p53信号通路，而SAMMSON和CARF同时敲低能有效的拮抗单独敲低SAMMSON引起的p53表达上调。因此提出假设：SAMMSON/CARF/p53信号轴参与调控BRAF突变黑色素瘤细胞对RAF抑制剂的适应性耐药。本项目拟以BRAF突变的黑色素瘤细胞作为研究模型，明确SAMMSON为黑色素瘤细胞中新的适应性耐药因子，阐明SAMMSON-CARF-p53信号轴介导黑色素瘤适应性耐药的分子机制及其对RAF抑制剂的肿瘤抑制效果的影响。本研究将为临床上克服黑色素瘤的适应性耐药提供新的靶点和治疗思路。

In human mutant BRAF melanoma cells, the clinical efficacy of RAF inhibitors is often comprised by adaptive resistance during the early stage of therapy. Our previous study has shown that long non-coding RNA SAMMSON (lncRNA SAMMSON) was rapidly induced by RAF inhibitor, and enhanced SAMMSON mediated adaptive resistance of mutant BRAF melanoma cells to RAF inhibitor. However, the molecular mechanism remains elusive. Moreover, SAMMSON silencing activates p53 signaling, and CARF knockdown efficiently blocked the induction of p53 by SAMMSON depletion. Therefore, we propose hypothesis that SAMMSON/CARF/p53 signaling axis modulates the adaptive resistance of mutant BRAF melanoma cells to RAF inhibitors. In this project, using mutant BRAF melanoma as the cell model, we aim to identify that SAMMSON is a newly mediator of adaptive resistance in melanoma. We then demonstrated the molecular mechanism of SAMMSON-CARF-p53 signaling axis mediated adaptive resistance to RAF inhibitor, and the effect of this signaling axis on tumor suppressive efficacy to RAF inhibitors. Thus, we will provide new targets in the clinical research in human mutant BRAF melanoma.