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

BRAF hyperactivates ERK and signals as a RAF inhibitor-sensitive monomer. Although RAF inhibitors can produce impressive clinical responses in patients with mutant 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 -mutant brain tumor treated with dabrafenib. Whole-exome sequencing revealed a secondary mutation at progression that was not present in the pretreatment tumor. Expressing BRAF 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-mediated resistance. Collectively, our results validate a novel biochemical mechanism of RAF inhibitor resistance mediated by a secondary mutation, emphasizing that, like driver mutations in cancer, the spectrum of mutations that drive resistance to targeted therapy are heterogeneous and perhaps emerge with a lineage-specific prevalence. In contrast to receptor tyrosine kinases, in which secondary mutations are often responsible for acquired resistance, second-site mutations in have not been validated in clinically acquired resistance to RAF inhibitors. We demonstrate a secondary mutation in (V600E/L514V) following progression on dabrafenib and confirm functionally that this mutation is responsible for resistance. .