Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncogene	38	16	2019 04	2994-3002	Oncogene

URL

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 (UniProt.org). 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