RAF小分子抑制剂在BRAF突变黑色素瘤细胞中诱导ERBB3转录表达的机制研究

RAF小分子抑制剂对BRAF基因突变肿瘤的临床治疗效果受到肿瘤适应性耐药的严重制约。以往研究发现RAF抑制剂能通过阻断BRAF突变肿瘤细胞中的ERK1/2信号诱导ERBB3受体分子的转录表达，进而激活其下游PI3K/AKT抗凋亡信号通路，引起肿瘤对RAF抑制剂的适应性耐受。然而ERK1/2信号的阻断是如何诱导ERBB3转录表达的这一关键科学问题尚未得到解答。本项目拟以BRAF基因突变的黑色素瘤为研究模型，阐明RAF抑制剂诱导ERBB3转录表达的分子机制及相关信号通路。首先寻找ERK1/2信号下游参与调控ERBB3表达的转录因子并解析其作用机制；其次研究ERK1/2信号对该转录因子转录功能的调控机制；最后在细胞及荷瘤裸鼠模型中检验靶向干扰该转录因子的表达对RAF抑制剂抑癌效果的影响。本项目不仅能完善人们对肿瘤适应性耐药机制的认识，也能为克服肿瘤对RAF抑制剂的适应性耐药提供新的靶点和思路。

The clinical efficacy of RAF inhibitors in treating mutant BRAF tumors is strongly comprised by adaptive resistance. Previous studies have shown that the upregulation of ERBB3 by ERK1/2 signal inhibition and activation of its downstream anti-apoptotic PI3K/AKT pathway is one of the most important and popular mechanisms of adaptive resistance. However, how ERBB3 expression is induced by blockade of ERK1/2 signaling remains unknown. Using mutant BRAF melanoma cell line models, we aim to unravel the molecular mechanisms of ERBB3 regulation by RAF inhibitors. We will first identify the transcription factor(s) downstream of ERK1/2 signaling that mediate the upregulation of ERBB3 and explore its functional mechanism. We will then study the regulation mechanism of the identified transcription factor by ERK1/2 signaling. Finally, we will investigate the impact of transcription factor depletion on the anti-tumor efficacy of RAF inhibitor in cell line and mouse xenograft models. These works will not only help us to better understand the regulatory mechanisms of adaptive resistance but also provide new therapeutic targets for treatment of resistant tumors.