Nature:研究者发现治疗癌症的新靶标
2016/09/13
近日,Nature上发表了一项研究揭示:KSR非活动状态的小分子稳定结构能够拮抗致癌基因RAS信号,该研究意味着可以鉴定发现一个或针对癌症治疗新靶点的蛋白。

杀伤T细胞环绕癌细胞(图片来源:NIH)

30%的人类恶性肿瘤与Ras基因突变有关

研究表明:约30%的人类恶性肿瘤与Ras基因突变有关。众所周知,Ras主要为活化控制基因转录的激酶,该蛋白是一种小G蛋白(分子量只有20~30KD),RAS信号途径是一种很常见的细胞分子信号传导途径,这一途径在细胞增殖、细胞调亡、细胞分化、癌变等方面起着重要的作用,尤其是与肿瘤细胞的生存、增殖、迁移、扩散、血管生成均有关系。

而Ras的激酶抑制因子KSR(一种支架蛋白)是由RAS激活的MAP激酶通路的假激酶,MAP激酶通路通过与RAF激酶二聚实现别构调节。

KSR非活动状态的小分子稳定结构能够拮抗RAS信号

近日,Nature上发表了一项研究揭示:KSR非活动状态的小分子稳定结构能够拮抗RAS信号,该研究意味着可以鉴定发现一个或针对癌症治疗新靶点的蛋白。

据悉,该研究由西奈山伊坎医学院Tisch癌症研究所(Tisch Cancer Institute at the Icahn School of Medicine)肿瘤科学和药理学助理教授Arvin Dar博士及同事完成。他们通过基于结构的方法发现了一种小分子,后者能稳定一种前所未知的KSR非活性状态。

图1:小分子APS-2-79模仿KSR等位基因,可以抑制肿瘤的Ras突变;且能够增加RAS突变细胞株内其他癌症药物的效力

图2:对绑定到KSR2–MEK1复合物上的APS-2-79 进行结构分析

这种KSR拮抗剂可与MEK抑制剂产生协同(synergy)效应,抑制RAS变异细胞系的生长,为靶向癌症中的致癌性RAS信号传导提供了一种潜在的治疗方法。

致癌基因Ras的靶向治疗研究现状

目前,依赖于Ras的癌症靶向治疗已有很多研究成果。人们一直在寻找依赖于Ras途径的新靶点,但由于Ras是肿瘤组织中最易突变的基因,但所以针对于Ras的癌症靶向治疗仍然受限。先前曾经有研究提出可能通过KSR实现对肿瘤的靶向治疗,但是有关药理学方法在此之前从未报道。

Ras是在细胞信号传导中发挥重要作用的小G蛋白,受上游信号的激活后磷酸化下游蛋白而产生一系列的级联反应。它参与了RAF-MEK-ERK这条调节通路的传导。RAF被RAS激活后激活下游的MEK,MEK进而激活ERK,活化的ERK进入细胞核,磷酸化特定基因上的特定位点,调控转录。

Arvin Dar教授表示,此项研究以KSR为靶点来研发新药,用来阻止Ras突变体的信号传递。KSR属于一大类蛋白,不仅参与肿瘤的发展,但同时还有其他疾病。靶向Ras的特定KSR蛋白可能对癌症的治疗有重要的意义,或将改善许多如肺癌、胰腺癌在内的侵略性癌症的治疗结果。

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  • Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling

    Deregulation of the Ras–mitogen activated protein kinase (MAPK) pathway is an early event in many different cancers and a key driver of resistance to targeted therapies1. Sustained signalling through this pathway is caused most often by mutations in K-Ras, which biochemically favours the stabilization of active RAF signalling complexes2. Kinase suppressor of Ras (KSR) is a MAPK scaffold3, 4, 5 that is subject to allosteric regulation through dimerization with RAF6, 7. Direct targeting of KSR could have important therapeutic implications for cancer; however, testing this hypothesis has been difficult owing to a lack of small-molecule antagonists of KSR function. Guided by KSR mutations that selectively suppress oncogenic, but not wild-type, Ras signalling, we developed a class of compounds that stabilize a previously unrecognized inactive state of KSR. These compounds, exemplified by APS-2-79, modulate KSR-dependent MAPK signalling by antagonizing RAF heterodimerization as well as the conformational changes required for phosphorylation and activation of KSR-bound MEK (mitogen-activated protein kinase kinase). Furthermore, APS-2-79 increased the potency of several MEK inhibitors specifically within Ras-mutant cell lines by antagonizing release of negative feedback signalling, demonstrating the potential of targeting KSR to improve the efficacy of current MAPK inhibitors. These results reveal conformational switching in KSR as a druggable regulator of oncogenic Ras, and further suggest co-targeting of enzymatic and scaffolding activities within Ras–MAPK signalling complexes as a therapeutic strategy for overcoming Ras-driven cancers.

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