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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.
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 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 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 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