Reference Detail

Ref Type

Journal Article

PMID

(31618628)

Authors

Botton T, Talevich E, Mishra VK, Zhang T, Shain AH, Berquet C, Gagnon A, Judson RL, Ballotti R, Ribas A, Herlyn M, Rocchi S, Brown KM, Hayward NK, Yeh I, Bastian BC

Title

Genetic Heterogeneity of BRAF Fusion Kinases in Melanoma Affects Drug Responses.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cell reports	29	3	2019 Oct 15	573-588.e7	Cell Rep

URL

Abstract Text

BRAF fusions are detected in numerous neoplasms, but their clinical management remains unresolved. We identified six melanoma lines harboring BRAF fusions representative of the clinical cases reported in the literature. Their unexpected heterogeneous responses to RAF and MEK inhibitors could be categorized upon specific features of the fusion kinases. Higher expression level correlated with resistance, and fusion partners containing a dimerization domain promoted paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway and hyperproliferation in response to first- and second-generation RAF inhibitors. By contrast, next-generation αC-IN/DFG-OUT RAF inhibitors blunted paradoxical activation across all lines and had their therapeutic efficacy further increased in vitro and in vivo by combination with MEK inhibitors, opening perspectives in the clinical management of tumors harboring BRAF fusions.

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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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	melanoma	sensitive	Lifirafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Lifirafenib (BGB-283) treatment inhibited viability of a melanoma cell line harboring BRAF V600E in culture (PMID: 31618628).	31618628
BRAF V600E	melanoma	sensitive	Tovorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Ojemda (tovorafenib) treatment inhibited viability of a melanoma cell line harboring BRAF V600E in culture (PMID: 31618628).	31618628
BRAF V600E	melanoma	sensitive	CCT196969	Preclinical - Cell culture	Actionable	In a preclinical study, CCT196969 treatment inhibited viability of a melanoma cell line harboring BRAF V600E in culture (PMID: 31618628).	31618628