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前沿综述:克服肿瘤对K-RasG12C抑制剂的耐药性

长久以来,针对癌基因KRAS的靶向药物的研发困难重重。近期的研究促使一系列全新的、针对KRASG12C突变的抑制剂问世,并在临床试验中取得了良好的治疗效果。然而,肿瘤细胞对于K-RasG12C抑制剂的耐药将大大降低这类新药的疗效。因此,阐明K-RasG12C抑制剂的耐药机制,并据此开发克服K-RasG12C抑制剂耐药性的治疗方法具有广泛而深远的临床意义。

最近,美国宾夕法尼亚州立大学的焦德龙博士和杨胜于教授撰写了关于如何克服肿瘤对K-RasG12C抑制剂耐药的前沿综述。

该综述首先简要介绍了K-Ras信号通路与癌症的关系及K-Ras靶向药物的研究现状,并深入探讨K-RasG12C抑制剂的固有及获得性耐药机制。随后,作者对近10年在克服K-RasG12C抑制剂耐药方面取得的成果进行了系统的归纳总结,并据此提出该领域亟待解决的科学问题和未来的主要研究方向。文章梗概如下:

21.png

图文摘要:K-RasG12C抑制剂的耐药机制(A,B)与治疗策略(C)

01
正常细胞中Ras蛋白的活化受生长因子及其受体的严格调控(图1)。

22.png

图1 Ras信号通路

02
RAS基因突变导致细胞增殖不受生长因子调控,进而诱发癌症。其中,KRASG12C突变主要发生在以肺癌,结肠癌和胰腺癌为代表的恶性肿瘤(表1)。

23.png

03
新型K-RasG12C抑制剂通过抑制K-RasG12C活化发挥作用,它的临床应用开创了针对KRAS突变肿瘤靶向治疗的新篇章(图2,表2)。

24.png

25.png

图2 K-RasG12C抑制剂的化学结构

04
肿瘤对K-RasG12C抑制剂的耐药可分为固有性耐药和获得性耐药。其中,不依赖MAPK/ERK通路的细胞增殖、次级KRAS基因突变、以及瘤内KRASG12C基因突变的异质性共同导致固有性耐药(图3)。然而,获得性K-RasG12C抑制剂耐药主要是由MAPK/ERK通路的代偿活化导致的(图4)。


26.png

图3 K-RasG12C抑制剂的固有耐药机制

27.png

图4 K-RasG12C抑制剂的获得性耐药机制

05
针对K-RasG12C与Ras信号通路垂直靶点的联合用药能够有效克服肿瘤对K-RasG12C靶向药物的耐药性(表3)。

06
K-RasG12C靶向治疗与常规化疗和免疫治疗有很好的协同作用,联合治疗能够导致持久、有效的肿瘤抑制(表3)。

28.png

综上,肿瘤细胞对K-RasG12C抑制剂的耐药机制分为固有性耐药和获得性耐药。联合治疗策略(K-RasG12C抑制剂 + 靶向治疗/免疫治疗/常规化疗方案)可在较长时期内有效控制肿瘤生长。

原文链接:https://www.cell.com/the-innovation/fulltext/S2666-6758(20)30035-7

作者简介

本论文的第一作者焦德龙和通讯作者杨胜于均来自美国宾夕法尼亚州立大学细胞生理系。

焦德龙:香港中文大学化学病理学博士,主要从事肿瘤靶向治疗及肿瘤免疫相关领域的研究。2016年至今先后就职于美国国立卫生院和宾夕法尼亚州立大学。目前已在Cell Research、Cellular & Molecular Immunology、Allergy、Cellular Immunology等杂志发表论文10余篇。

杨胜于:杨教授主要从事肿瘤细胞转移的机制研究,目前已在细胞信号传导、细胞迁移、细胞骨架组装等领域取得了重要成果。曾在Nature、Cancer Cell、Cancer Research、Gastroenterology、Cell Report等杂志发表论文40余篇。

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