A Secondary Mutation in BRAF Confers Resistance to RAF Inhibition in a BRAF^V600E-Mutant Brain Tumor.

ABSTRACT: BRAF^V600E hyperactivates ERK and signals as a RAF inhibitor-sensitive monomer. Although RAF inhibitors can produce impressive clinical responses in patients with mutant BRAF tumors, the mechanisms of resistance to these drugs are incompletely characterized. Here, we report a complete response followed by clinical progression in a patient with a BRAF^V600E-mutant brain tumor treated with dabrafenib. Whole-exome sequencing revealed a secondary BRAF^L514V mutation at progression that was not present in the pretreatment tumor. Expressing BRAF^V600E/L514V induces ERK signaling, promotes RAF dimer formation, and is sufficient to confer resistance to dabrafenib. Newer RAF dimer inhibitors and an ERK inhibitor are effective against BRAF

SUBMITTER: Wang J 

PROVIDER: S-EPMC6125191 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature