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ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma

 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 
 NATURE, Vol.594(7863) : 418-418, 2021-06 
Journal Title
Issue Date
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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Shin, Sang Joon(신상준) ORCID logo https://orcid.org/0000-0001-5350-7241
Jung, Min Kyu(정민규) ORCID logo https://orcid.org/0000-0001-8281-3387
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