Abstract |
BRAF mutations are frequently observed in melanoma and hairy-cell leukemia. Currently approved rapidly accelerated fibrosarcoma ( RAF) kinase inhibitors targeting oncogenic BRAF V600 mutations have shown remarkable efficacy in the clinic, but their therapeutic benefits are occasionally hampered by acquired resistance due to RAF dimerization-dependent reactivation of the downstream MAPK pathway, which is known as paradoxical activation. There is also a concern that paradoxical activation of the MAPK pathway may trigger secondary cancer progression. In this study, we developed chimeric compounds, proteolysis targeting chimeras ( PROTACs), that target BRAFV600E protein for degradation. CRBN(BRAF)-24, the most effective chimera, potently degraded BRAFV600E in a ubiquitin- proteasome system (UPS)-dependent manner and inhibited the proliferation of BRAFV600E -driven cancer cells. In BRAF wild-type cells, CRBN(BRAF)-24 induced neither BRAFWT degradation nor paradoxical activation of the MAPK pathway. Biochemical analysis revealed that CRBN(BRAF)-24 showed more potent and sustained suppression of MAPK signaling than a BRAFV600E inhibitor, PLX-8394, in BRAFV600E -driven cancer cells. Targeted degradation of BRAFV600E by CRBN(BRAF)-24 could be a promising strategy to evade paradoxical activation of the RAF-MAPK pathway.
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Authors | Nobumichi Ohoka, Masanori Suzuki, Takuya Uchida, Yoshinori Tsukumo, Masayuki Yoshida, Takao Inoue, Hitoshi Ohki, Mikihiko Naito |
Journal | Cancer science
(Cancer Sci)
Vol. 113
Issue 8
Pg. 2828-2838
(Aug 2022)
ISSN: 1349-7006 [Electronic] England |
PMID | 35579105
(Publication Type: Journal Article)
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Copyright | © 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. |
Chemical References |
- Protein Kinase Inhibitors
- BRAF protein, human
- Proto-Oncogene Proteins B-raf
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Topics |
- Cell Line, Tumor
- Humans
- MAP Kinase Signaling System
- Melanoma
(drug therapy, genetics)
- Mutation
- Protein Kinase Inhibitors
(pharmacology)
- Proto-Oncogene Proteins B-raf
(antagonists & inhibitors, metabolism)
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