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Cited by 138Melanoma and MAPK PathwaysProtein Kinase Regulation and GTPase SignalingLung Cancer Treatments and Mutations

The DOI matches its Crossref record; 61 of the 61 references it cites were found in a registry or an index.

ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma

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Yen, Ivana, Shanahan, Frances, Lee, Jeeyun, Hong, Yong Sang, Shin, Sang Joon, Moore, Amanda R., Sudhamsu, Jawahar, Chang, Matthew T., Bae, Inhwan, Dela Cruz, Darlene, Hunsaker, Thomas, Klijn, Christiaan, Liau, Nicholas P. D., Lin, Eva, Martin, Scott E., Modrusan, Zora, Piskol, Robert, Segal, Ehud, Venkatanarayan, Avinashnarayan, Ye, Xin, Yin, Jianping, Zhang, Liangxuan, Kim, Jin-Soo, Lim, Hyeong-Seok, Kim, Kyu-Pyo, Kim, Yu Jung, Han, Hye Sook, Lee, Soo Jung, Kim, Seung Tae, Jung, Minkyu, Hong, Yoon-hee, Noh, Young Su, Choi, Munjeong, Han, Oakpil, Nowicka, Malgorzata, Srinivasan, Shrividhya, Yan, Yibing, Kim, Tae Won, Malek, Shiva·2021·Nature
DOI 10.1038/s41586-021-03515-1
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Abstract

Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAF V600-mutant melanoma, they are ineffective in non-BRAF V600 mutant cells 1-3. Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAF V600E- 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 BRAF V600E- 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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Authors
Yen, I., Shanahan, F., Lee, J., Hong, Y. S., Shin, S. J., Moore, A. R., Sudhamsu, J., Chang, M. T., Bae, I., Dela Cruz, D., Hunsaker, T., Klijn, C., Liau, N. P. D., Lin, E., Martin, S. E., Modrusan, Z., Piskol, R., Segal, E., Venkatanarayan, A., Ye, X., Yin, J., Zhang, L., Kim, J.-S., Lim, H.-S., Kim, K.-P., Kim, Y. J., Han, H. S., Lee, S. J., Kim, S. T., Jung, M., Hong, Y.-H., Noh, Y. S., Choi, M., Han, O., Nowicka, M., Srinivasan, S., Yan, Y., Kim, T. W., & Malek, S.
Affiliations
  • Genentech (US)
  • Samsung Medical Center (KR)
  • Asan Medical Center (KR)
  • Yonsei University (KR)
  • Hanmi Pharmaceutical (South Korea) (KR)
  • Seoul National University (KR)
  • Chungbuk National University (KR)
  • Kyungpook National University (KR)
Corresponding author
  • Kim, Seung Tae
  • Kim, Tae Won
  • Malek, Shiva
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2021-05-05
Volume
594
Issue
7863
Pages
418-423
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-021-03515-1
OpenAlex
W3157426342
Cited by
138
References
61
Citations by year
2026: 19 · 2025: 33 · 2024: 31 · 2023: 25 · 2022: 22 · 2021: 8
FWCI
6.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords
drug resistance, melanoma, NRAS-mutant melanoma, BRAF V600E mutation, circulating tumor DNA
MeSH terms
Animals, Cell Line, Female, Humans, Melanoma, Mutation, Drug Resistance, Neoplasm, Cell Line, Tumor, raf Kinases, Proto-Oncogene Proteins A-raf, Mice, Protein Multimerization

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