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Updated: Jul 3, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

在结直肠癌中,RAS/RAF转换和ERBB2复制数调节HER2异质性和对HER2导向疗法的响应性

Harshabad Singh¹, Pranshu Sahgal^1,2, Kevin Kapner¹

¹Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

Clinical cancer research : an official journal of the American Association for Cancer Research

|February 12, 2024

概括

具有RAS/RAF变化的ERBB2增强结直肠癌显示对trastuzumab的耐药性,但仍然对trastuzumab敏感. 这一发现突出了一个独特的分子亚型,对结直肠癌患者具有独特的治疗影响.

科学领域:

在瘤学瘤学.
基因组学就是基因组学.
分子生物学分子生物学

背景情况:

ERBB2增强结直肠癌 (CRC) 是一种独特的分子亚型,具有新兴的治疗选择.
同时发生的瘤性RAS/RAF变异对ERBB2增强CRC治疗结果的影响仍然基本未知.

研究的目的:

调查ERBB2增强结直肠癌中同时发生的瘤性RAS/RAF变化的影响.
了解这种特定的CRC亚型中对HER2导向疗法的不同反应和抵抗模式.

主要方法:

大型CRC队列的基因组分析 (Dana-Farber,Foundation Medicine Inc.) 以确定ERBB2增强的病例.
对接受 HER2 定向治疗的患者结果的分析.
使用IHC和基因组分析评估HER2的内和间异质性.
使用同源性CRC细胞系进行体外和异种移植研究,以评估RAS转换对治疗有效性的影响.

主要成果:

在左侧的CRC中,ERBB2放大更频繁.
大约20%的ERBB2放大CRC携带RAS/RAF同时发生的变化.
与RAS/RAF野生型病例相比,与RAS/RAF野生型病例相比,具有RAS/RAF变化的结肠直肠癌呈现较低水平的ERBB2放大,增加了内异质性,以及间ERBB2异调.
具有RAS/RAF变化的ERBB2增强CRC表现出对基于trastuzumab的组合 (例如,trastuzumab/tucatinib) 的耐药性,但在临床前模型中保留了对trastuzumab deruxtecan的敏感性.
特拉斯图祖马布德鲁克斯坦在患有高水平ERBB2增强,RAS/RAF覆盖的CRC的患者中显示出临床疗效.

结论:

同时发生的RAS/RAF变异定义了一个独特的ERBB2-增强型CRC亚型,其特点是异质性增加和对某些HER2-向疗法的耐药性.
特拉斯图祖马布德鲁克斯坦是ERBB2增强结直肠癌与同时发生的RAS/RAF变化的有前途的治疗选择.
在这个未研究的CRC队列中,需要对trastuzumab deruxtecan进行进一步的临床研究.

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