Simultaneous blocking of the pan‐RAF and S100B pathways as a synergistic therapeutic strategy against malignant melanoma

Melanoma is a very aggressive form of skin cancer. Although BRAF inhibitors have been utilized for melanoma therapy, advanced melanoma patients still face a low five‐year survival rate. Recent studies have shown that CRAF can compensate for BRAF depletion via regulating DNA synthesis to remain melan...

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Bibliographic Details
Published in:Journal of cellular and molecular medicine 2021-02, Vol.25 (4), p.1972-1981
Main Authors: Wu, Ke‐Jia, Ho, Shih‐Hsin, Wu, Chun, Wang, Hui‐Min D., Ma, Dik‐Lung, Leung, Chung‐Hang
Format: Article
Language:English
Subjects:
Animal models
Animals
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Apoptosis
Cancer therapies
Cell growth
Cell Line, Tumor
Cell proliferation
Cell Proliferation - drug effects
Cytotoxicity
Disease Models, Animal
DNA biosynthesis
DNA Replication
drug discovery
Experiments
Female
Flow cytometry
Humans
Kidney cancer
Kinases
Laboratory animals
Ligands
malignant melanoma
MAP Kinase Signaling System - drug effects
Melanoma
Melanoma - drug therapy
Melanoma - etiology
Melanoma - metabolism
Melanoma - pathology
Mice
Original
p53 Protein
pan‐RAF
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - therapeutic use
Proteins
Proto-Oncogene Proteins c-raf - metabolism
Raf protein
S100 Calcium Binding Protein beta Subunit - metabolism
S100b protein
S100B‐p53 interaction
Signal Transduction - drug effects
Skin cancer
Statistical analysis
synergistic
Transcription
Tumors
Variance analysis
Xenograft Model Antitumor Assays
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Summary:Melanoma is a very aggressive form of skin cancer. Although BRAF inhibitors have been utilized for melanoma therapy, advanced melanoma patients still face a low five‐year survival rate. Recent studies have shown that CRAF can compensate for BRAF depletion via regulating DNA synthesis to remain melanoma proliferation. Hence, targeting CRAF either alone or in combination with other protein pathways is a potential avenue for melanoma therapy. Based on our previously reported CRAF‐selective inhibitor for renal cancer therapy, we have herein discovered an analogue (complex 1) from the reported CRAF library suppresses melanoma cell proliferation and melanoma tumour growth in murine models of melanoma via blocking the S100B and RAF pathways. Intriguingly, we discovered that inhibiting BRAF together with S100B exerts a novel synergistic effect to significantly restore p53 transcription activity and inhibit melanoma cell proliferation, whereas blocking BRAF together with CRAF only had an additive effect. We envision that blocking the pan‐RAF and S100B/p53 pathways might be a novel synergistic strategy for melanoma therapy and that complex 1 is a potential inhibitor against melanoma via blocking the pan‐RAF and S100B pathways.
ISSN:1582-1838
1582-4934
DOI:10.1111/jcmm.15994