小柯机器人

美国基因泰克公司Shiva Malek、韩国蔚山大学Tae Won Kim等研究人员发现，ARAF突变赋予黑色素瘤中RAF抑制剂belvarafenib的耐药性。2021年5月5日，《自然》杂志在线发表了这项成果。

研究人员表示，尽管RAF单体抑制剂（I.5型，BRAF（V600）型）在临床上已被批准用于治疗BRAF^V600突变型黑色素瘤，但它们在非BRAF^V600突变型细胞中无效。belvarafenib是一种有效的选择性RAF二聚体（II型）抑制剂，并在患有BRAF^V600E和NRAS突变的黑色素瘤患者中表现出临床活性。

研究人员报告了第一阶段的研究，该研究旨在测试最大耐受剂量，并评估了belvarafenib在BRAF^V600E和RAS突变的晚期实体瘤中的安全性和初步疗效（NCT02405065，NCT03118817）。通过产生耐belvarafenib的NRAS突变黑素瘤细胞并分析来自使用belvarafenib治疗患者的循环肿瘤DNA，研究人员在激酶结构域内发现了ARAF中的新复发突变。ARAF突变体以二聚体和激酶活性依赖性方式赋予了对belvarafenib的抗药性。

belvarafenib诱导了ARAF突变体二聚体，而含有突变体ARAF的二聚体在抑制剂存在下具有活性。ARAF突变可能充当RAF二聚体抑制剂的通用耐药机制，因为该突变体对一组II型RAF抑制剂的敏感性降低。RAF加MEK抑制的组合可用于延迟ARAF驱动的耐药性，并为临床使用提供合理的组合。总之，这些发现揭示了ARAF亚型的特异性和补偿功能，并暗示了ARAF突变是对RAF二聚体抑制剂产生耐药的驱动力。

附：英文原文

Title: ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma

Author: Ivana Yen, Frances Shanahan, Jeeyun Lee, Yong Sang Hong, Sang Joon Shin, Amanda R. Moore, Jawahar Sudhamsu, Matthew T. Chang, Inhwan Bae, Darlene Dela Cruz, Thomas Hunsaker, Christiaan Klijn, Nicholas P. D. Liau, Eva Lin, Scott E. Martin, Zora Modrusan, Robert Piskol, Ehud Segal, Avinashnarayan Venkatanarayan, Xin Ye, Jianping Yin, Liangxuan Zhang, Jin-Soo Kim, Hyeong-Seok Lim, Kyu-Pyo Kim, Yu Jung Kim, Hye Sook Han, Soo Jung Lee, Seung Tae Kim, Minkyu Jung, Yoon-hee Hong, Young Su Noh, Munjeong Choi, Oakpil Han, Malgorzata Nowicka, Shrividhya Srinivasan, Yibing Yan, Tae Won Kim, Shiva Malek, Ivana Yen, Frances Shanahan, Jeeyun Lee, Yong Sang Hong, Sang Joon Shin, Amanda R. Moore, Jawahar Sudhamsu, Matthew T. Chang, Inhwan Bae, Darlene Dela Cruz, Thomas Hunsaker, Christiaan Klijn, Nicholas P. D. Liau, Eva Lin, Scott E. Martin, Zora Modrusan, Robert Piskol, Ehud Segal, Avinashnarayan Venkatanarayan, Xin Ye, Jianping Yin, Liangxuan Zhang, Jin-Soo Kim, Hyeong-Seok Lim, Kyu-Pyo Kim, Yu Jung Kim, Hye Sook Han, Soo Jung Lee, Seung Tae Kim, Minkyu Jung, Yoon-hee Hong, Young Su Noh, Munjeong Choi, Oakpil Han

Issue&Volume: 2021-05-05

Abstract: Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAFV600-mutant melanoma, they are ineffective in non-BRAFV600 mutant cells1,2,3. Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAFV600E- and NRAS-mutant melanomas. Here we report the first-in-human phase I study investigating the maximum tolerated dose, and assessing the safety and preliminary efficacy of belvarafenib in BRAFV600E- and RAS-mutated advanced solid tumours (NCT02405065, NCT03118817). By generating belvarafenib-resistant NRAS-mutant melanoma cells and analysing circulating tumour DNA from patients treated with belvarafenib, we identified new recurrent mutations in ARAF within the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer- and a kinase activity-dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAF mutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of type II RAF inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAF mutations as a driver of resistance to RAF dimer inhibitors.

DOI: 10.1038/s41586-021-03515-1

Source: https://www.nature.com/articles/s41586-021-03515-1

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