ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma

突变体 黑色素瘤 突变 MEK抑制剂 癌症研究 激酶 生物 神经母细胞瘤RAS病毒癌基因同源物 药理学 医学 遗传学 MAPK/ERK通路 基因 克拉斯
作者
Ivana Yen,Fergus 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 Modrušan,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,Małgorzata Nowicka,Shrividhya Srinivasan,Yibing Yan,Tae Won Kim,Shiva Malek
出处
期刊:Nature [Springer Nature]
卷期号:594 (7863): 418-423 被引量:76
标识
DOI:10.1038/s41586-021-03515-1
摘要

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 cells1–3. 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. The development, characterization and phase I clinical testing of the RAF inhibitor belvarafenib in cancer and a new resistance mechanism mediated by ARAF mutations are described.
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