A Secondary Mutation in <i>BRAF</i> Confers Resistance to RAF Inhibition in a <i>BRAF</i> 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 <i>BRAF</i> 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 <i>BRAF</i>^V600E-mutant brain tumor treated with dabrafenib. Whole-exome sequencing revealed a secondary <i>BRAF</i>^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^L514V-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.<b>Significance:</b> In contrast to receptor tyrosine kinases, in which secondary mutations are often responsible for acquired resistance, second-site mutations in <i>BRAF</i> have not been validated in clinically acquired resistance to RAF inhibitors. We demonstrate a secondary mutation in <i>BRAF</i> (V600E/L514V) following progression on dabrafenib and confirm functionally that this mutation is responsible for resistance. <i>Cancer Discov; 8(9); 1130-41. ©2018 AACR.</i><i>See related commentary by Romano and Kwong, p. 1064</i><i>This article is highlighted in the In This Issue feature, p. 1047</i>.