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
Open accessAbstract
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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“Several groups have reported that resistance clones are not preexisting but occur via epigenetic adaptation of drug-tolerant persisters whereby some undergo further evolution to acquire genetic resistance mechanisms (45–47).”
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Metadata
- 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
- Lee, Jeeyun
- Hong, Yong Sang
- Shin, Sang Joon
- Moore, Amanda R.
- Sudhamsu, Jawahar
- Bae, Inhwan
- Hunsaker, Thomas
- Klijn, Christiaan
- Liau, Nicholas P. D.
- Lin, Eva
- Martin, Scott E.
- Modrusan, Zora
- Piskol, Robert
- Venkatanarayan, Avinashnarayan
- Ye, Xin
- Yin, Jianping
- Kim, Jin-Soo
- Kim, Kyu-Pyo
- Kim, Yu Jung
- Han, Hye Sook
- Lee, Soo Jung
- Kim, Seung Tae
- Jung, Minkyu
- Hong, Yoon-hee
- Noh, Young Su
- Kim, Tae Won
- Malek, Shiva
- Venue
- Nature
- Published
- 2021-05-05
- Volume
- 594
- Issue
- 7863
- Pages
- 418-423
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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
- green
- www.nature.com
- 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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