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Ref Type Journal Article
PMID (30575814)
Authors Khater F, Langlois S, Cassart P, Roy AM, Lajoie M, Healy J, Richer C, St-Onge P, Piché N, Perreault S, Cellot S, Marzouki M, Jabado N, Sinnett D
Title Recurrent somatic BRAF insertion (p.V504_R506dup): a tumor marker and a potential therapeutic target in pilocytic astrocytoma.
Abstract Text Pilocytic astrocytoma (PA) is emerging as a tumor entity with dysregulated RAS/RAF/MEK/ERK signaling. In this study, we report the identification of a novel recurrent BRAF insertion (p.V504_R506dup) in five PA cases harboring exclusively this somatic tandem duplication. This recurrent alteration leads to an addition of three amino acids in the kinase domain of BRAF and has functional impact on activating MAPK phosphorylation. Importantly, we show that this mutation confers resistance to RAF inhibitors without changing effectiveness while downstream MEK inhibitors remain effective. Our results further emphasize the importance of BRAF alterations in PA and the need to characterize them in a given tumor as this can affect therapeutic strategies and their potential use as tumor marker in molecular diagnostics.


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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 V504_R506dup duplication gain of function BRAF V504_R506dup (also referred to as R506_K507insVLR) indicates the insertion of three amino acids, valine (V)-504 through arginine (R)-506, in the protein kinase domain of the Braf protein ( V504_R506dup confers a gain of function to the Braf protein as demonstrated by stabilization of Braf homodimers, increased downstream Erk phosphorylation in cultured cells (PMID: 23817572, PMID: 30575814), and association with increased Erk1/2 phosphorylation in human tumor samples (PMID: 29544532), and has been associated with resistance to select Raf and Mek inhibitors in cultured cells (PMID: 30575814). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V504_R506dup Advanced Solid Tumor predicted - resistant Sorafenib Preclinical - Biochemical Actionable In a preclinical study, transformed cells overexpressing BRAF V504_R506dup were resistant to Nexavar (sorafenib) in culture (PMID: 30575814). 30575814
BRAF V504_R506dup Advanced Solid Tumor resistant Vemurafenib Preclinical - Biochemical Actionable In a preclinical study, transformed cells overexpressing BRAF V504_R506dup were resistant to Zelboraf (vemurafenib) in culture (PMID: 30575814). 30575814
BRAF V504_R506dup Advanced Solid Tumor sensitive Trametinib Preclinical - Biochemical Actionable In a preclinical study, Mekinist (trametinib) treatment resulted in decreased Erk1/2 phosphorylation in transformed cells expressing BRAF V504_R506dup in culture (PMID: 30575814). 30575814