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Ref Type Journal Article
PMID (34108213)
Authors Yap J, Deepak RNVK, Tian Z, Ng WH, Goh KC, Foo A, Tee ZH, Mohanam MP, Sim YRM, Degirmenci U, Lam P, Chen Z, Fan H, Hu J
Title The stability of R-spine defines RAF inhibitor resistance: A comprehensive analysis of oncogenic BRAF mutants with in-frame insertion of αC-β4 loop.
Journal Vol Issue Date Pages Journal Short Title
Science advances 7 24 2021 06 Sci Adv
URL
Abstract Text Although targeting BRAF mutants with RAF inhibitors has achieved promising outcomes in cancer therapy, drug resistance remains a remarkable challenge, and underlying molecular mechanisms are not fully understood. Here, we characterized a previously unknown group of oncogenic BRAF mutants with in-frame insertions (LLRins506 or VLRins506) of αC-β4 loop. Using structure modeling and molecular dynamics simulation, we found that these insertions formed a large hydrophobic network that stabilizes R-spine and thus triggers the catalytic activity of BRAF. Furthermore, these insertions disrupted BRAF dimer interface and impaired dimerization. Unlike BRAF(V600E), these BRAF mutants with low dimer affinity were strongly resistant to all RAF inhibitors in clinic or clinical trials, which arises from their stabilized R-spines. As predicted by molecular docking, the stabilized R-spines in other BRAF mutants also conferred drug resistance. Together, our data indicated that the stability of R-spine but not dimer affinity determines the RAF inhibitor resistance of oncogenic BRAF mutants.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
BRAF R506_K507insLLR insertion gain of function BRAF R506_K507insLLR results in the insertion of three amino acids in the protein kinase domain of the Braf protein between amino acids 506 and 507 (UniProt.org). R506_K507insLLR results in impaired Braf homodimerization and heterodimerization, confers resistance to RAF inhibitors, and leads to increased phosphorylation of Erk1/2 and downstream signaling, and foci formation in cultured cells (PMID: 34108213). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF L485F Advanced Solid Tumor predicted - resistant Dabrafenib Preclinical - Biochemical Actionable In a preclinical study, cells expressing BRAF L485F were resistant to treatment with Tafinlar (dabrafenib) in culture (PMID: 34108213). 34108213
BRAF R506_K507insLLR Advanced Solid Tumor resistant PLX8394 Preclinical - Cell line xenograft Actionable In a preclinical study, cells expressing BRAF R506_K507insLLR were resistant to treatment with PLX8394 in culture and cell line xenograft models (PMID: 34108213). 34108213
BRAF V504_R506dup Advanced Solid Tumor predicted - resistant Sorafenib Preclinical - Biochemical Actionable In a preclinical study, cells expressing BRAF V504_R506dup were resistant to treatment with Nexavar (sorafenib) in culture (PMID: 34108213). 34108213
BRAF R506_K507insLLR Advanced Solid Tumor resistant Dabrafenib Preclinical - Cell line xenograft Actionable In a preclinical study, cells expressing BRAF R506_K507insLLR were resistant to treatment with Tafinlar (dabrafenib) in culture and cell line xenograft models (PMID: 34108213). 34108213
BRAF L505H Advanced Solid Tumor predicted - resistant Vemurafenib Preclinical - Biochemical Actionable In a preclinical study, cells expressing BRAF L505H were resistant to treatment with Zelboraf (vemurafenib) in culture (PMID: 34108213). 34108213
BRAF V504_R506dup Advanced Solid Tumor resistant Vemurafenib Preclinical - Cell line xenograft Actionable In a preclinical study, cells expressing BRAF V504_R506dup were resistant to treatment with Zelboraf (vemurafenib) in culture and cell line xenograft models (PMID: 34108213). 34108213
BRAF L505H Advanced Solid Tumor predicted - resistant Dabrafenib Preclinical - Biochemical Actionable In a preclinical study, cells expressing BRAF L505H were resistant to treatment with Tafinlar (dabrafenib) in culture (PMID: 34108213). 34108213
BRAF R506_K507insLLR Advanced Solid Tumor predicted - resistant Sorafenib Preclinical - Biochemical Actionable In a preclinical study, cells expressing BRAF R506_K507insLLR were resistant to treatment with Nexavar (sorafenib) in culture (PMID: 34108213). 34108213
BRAF R506_K507insLLR Advanced Solid Tumor predicted - sensitive Binimetinib Preclinical - Biochemical Actionable In a preclinical study, Mektovi (binimetinib) treatment inhibited Erk signaling in cells expressing BRAF R506_K507insLLR in culture (PMID: 34108213). 34108213
BRAF V504_R506dup Advanced Solid Tumor predicted - resistant LY3009120 Preclinical - Biochemical Actionable In a preclinical study, cells expressing BRAF V504_R506dup were resistant to treatment with LY3009120 in culture (PMID: 34108213). 34108213
BRAF L485F Advanced Solid Tumor predicted - sensitive LY3009120 Preclinical - Biochemical Actionable In a preclinical study, LY3009120 treatment inhibited Erk signaling in cells expressing BRAF L485F in culture (PMID: 34108213). 34108213
BRAF R506_K507insLLR Advanced Solid Tumor sensitive Trametinib Preclinical - Cell line xenograft Actionable In a preclinical study, Mekinist (trametinib) treatment resulted in decreased Erk signaling in cultured cells expressing BRAF R506_K507insLLR and inhibited tumor growth in cell line xenograft models (PMID: 34108213). 34108213
BRAF V504_R506dup Advanced Solid Tumor resistant PLX8394 Preclinical - Cell line xenograft Actionable In a preclinical study, cells expressing BRAF V504_R506dup were resistant to treatment with PLX8394 in culture and cell line xenograft models (PMID: 34108213). 34108213
BRAF R506_K507insLLR Advanced Solid Tumor predicted - sensitive Cobimetinib Preclinical - Biochemical Actionable In a preclinical study, Cotellic (cobimetinib) treatment inhibited Erk signaling in cells expressing BRAF R506_K507insLLR in culture (PMID: 34108213). 34108213
BRAF R506_K507insLLR Advanced Solid Tumor resistant Vemurafenib Preclinical - Cell line xenograft Actionable In a preclinical study, cells expressing BRAF R506_K507insLLR were resistant to treatment with Zelboraf (vemurafenib) in culture and cell line xenograft models (PMID: 34108213). 34108213
BRAF R506_K507insLLR Advanced Solid Tumor predicted - resistant LY3009120 Preclinical - Biochemical Actionable In a preclinical study, cells expressing BRAF R506_K507insLLR were resistant to treatment with LY3009120 in culture (PMID: 34108213). 34108213
BRAF L505H Advanced Solid Tumor predicted - resistant LY3009120 Preclinical - Biochemical Actionable In a preclinical study, cells expressing BRAF L505H were resistant to treatment with LY3009120 in culture (PMID: 34108213). 34108213
BRAF L505H Advanced Solid Tumor predicted - resistant PLX8394 Preclinical - Biochemical Actionable In a preclinical study, cells expressing BRAF L505H were resistant to treatment with PLX8394 in culture (PMID: 34108213). 34108213
BRAF L485F Advanced Solid Tumor predicted - resistant Vemurafenib Preclinical - Biochemical Actionable In a preclinical study, cells expressing BRAF L485F were resistant to treatment with Zelboraf (vemurafenib) in culture (PMID: 34108213). 34108213
BRAF V504_R506dup Advanced Solid Tumor sensitive Trametinib Preclinical - Cell line xenograft Actionable In a preclinical study, Mekinist (trametinib) treatment resulted in decreased Erk signaling in cultured cells expressing BRAF V504_R506dup and inhibited tumor growth in cell line xenograft models (PMID: 34108213). 34108213
BRAF R506_K507insLLR Advanced Solid Tumor predicted - sensitive Selumetinib Preclinical - Biochemical Actionable In a preclinical study,Koselugo (selumetinib) treatment inhibited Erk signaling in cells expressing BRAF R506_K507insLLR in culture (PMID: 34108213). 34108213
BRAF V504_R506dup Advanced Solid Tumor resistant Dabrafenib Preclinical - Cell line xenograft Actionable In a preclinical study, cells expressing BRAF V504_R506dup were resistant to treatment with Tafinlar (dabrafenib) in culture and cell line xenograft models (PMID: 34108213). 34108213
BRAF L485F Advanced Solid Tumor predicted - resistant PLX8394 Preclinical - Biochemical Actionable In a preclinical study, cells expressing BRAF L485F were resistant to treatment with PLX8394 in culture (PMID: 34108213). 34108213