<i>BRAF</i> Fusion as a Novel Mechanism of Acquired Resistance to Vemurafenib in <i>BRAF</i>^V600E Mutant Melanoma.

Abstract

<b>Purpose:</b> Many patients with <i>BRAF^V</i>^600E mutant melanoma treated with BRAF inhibitors experience a rapid response, but ultimately develop resistance. Insight into the mechanism of resistance is critical for development of more effective treatment strategies.<b>Experimental Design:</b> Comprehensive genomic profiling of serial biopsies was performed in a patient with a <i>BRAF</i>^V600E mutant metastatic melanoma who developed resistance to vemurafenib. An <i>AGAP3-BRAF</i> fusion gene, identified in the vemurafenib-resistant tumor, was expressed in <i>BRAF</i>^V600E melanoma cell lines, and its effect on drug sensitivity was evaluated.<b>Results:</b> Clinical resistance to vemurafenib in a melanoma harboring a <i>BRAF</i>^V600E mutation was associated with acquisition of an <i>AGAP3-BRAF</i> fusion gene. Expression of the <i>AGAP3-BRAF</i> fusion in <i>BRAF</i>^V600E mutant melanoma cells induced vemurafenib resistance; however, these cells remained relatively sensitive to MEK inhibitors. The patient experienced clinical benefit following treatment with the combination of a BRAF and a MEK inhibitor. Rebiopsy of the tumor at a later time point, after BRAF and MEK inhibitors had been discontinued, showed loss of the <i>AGAP3-BRAF</i> fusion gene. Mixing experiments suggest that cells harboring both <i>BRAF</i>^V600E and <i>AGAP3-BRAF</i> only have a fitness advantage over parental <i>BRAF</i>^V600E cells during active treatment with a BRAF inhibitor.<b>Conclusions:</b> We report acquisition of a <i>BRAF</i> fusion as a novel mechanism of acquired resistance to vemurafenib in a patient with melanoma harboring a <i>BRAF</i>^V600E mutation. The acquisition and regression of clones harboring this fusion during the presence and absence of a BRAF inhibitor are consistent with rapidly evolving clonal dynamics in melanoma. <i>Clin Cancer Res; 23(18); 5631-8. ©2017 AACR</i>.