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 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 () and Shiva Malek ()
Additional contact information
Ivana Yen: Genentech Inc.
Frances Shanahan: Genentech Inc.
Jeeyun Lee: Sungkyunkwan University School of Medicine
Yong Sang Hong: University of Ulsan College of Medicine
Sang Joon Shin: Yonsei University College of Medicine
Amanda R. Moore: Genentech Inc.
Jawahar Sudhamsu: Genentech Inc.
Matthew T. Chang: Genentech Inc.
Inhwan Bae: Hanmi Pharmaceutical Co., Ltd.
Darlene Cruz: Genentech Inc.
Thomas Hunsaker: Genentech Inc.
Christiaan Klijn: Genentech Inc.
Nicholas P. D. Liau: Genentech Inc.
Eva Lin: Genentech Inc.
Scott E. Martin: Genentech Inc.
Zora Modrusan: Genentech Inc.
Robert Piskol: Genentech Inc.
Ehud Segal: Genentech Inc.
Avinashnarayan Venkatanarayan: Genentech Inc.
Xin Ye: Genentech Inc.
Jianping Yin: Genentech Inc.
Liangxuan Zhang: Genentech Inc.
Jin-Soo Kim: Seoul National University Boramae Medical Center
Hyeong-Seok Lim: Asan Medical Center, University of Ulsan College of Medicine
Kyu-Pyo Kim: University of Ulsan College of Medicine
Yu Jung Kim: Seoul National University Bundang Hospital, Seoul National University College of Medicine
Hye Sook Han: Chungbuk National University Hospital, Chungbuk National University College of Medicine
Soo Jung Lee: Kyungpook National University Chilgok Hospital, Kyungpook National University
Seung Tae Kim: Sungkyunkwan University School of Medicine
Minkyu Jung: Yonsei University College of Medicine
Yoon-hee Hong: Hanmi Pharmaceutical Co., Ltd.
Young Su Noh: Hanmi Pharmaceutical Co., Ltd.
Munjeong Choi: Hanmi Pharmaceutical Co., Ltd.
Oakpil Han: Hanmi Pharmaceutical Co., Ltd.
Malgorzata Nowicka: Genentech Inc.
Shrividhya Srinivasan: Genentech Inc.
Yibing Yan: Genentech Inc.
Tae Won Kim: University of Ulsan College of Medicine
Shiva Malek: Genentech Inc.

Nature, 2021, vol. 594, issue 7863, 418-423

Abstract: 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 cells1–3. 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.

Date: 2021
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DOI: 10.1038/s41586-021-03515-1

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