Purpose: Many patients with BRAF^V^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.Experimental Design: Comprehensive genomic profiling of serial biopsies was performed in a patient with a BRAF^V600E mutant metastatic melanoma who developed resistance to vemurafenib. An AGAP3-BRAF fusion gene, identified in the vemurafenib-resistant tumor, was expressed in BRAF^V600E melanoma cell lines, and its effect on drug sensitivity was evaluated.Results: Clinical resistance to vemurafenib in a melanoma harboring a BRAF^V600E mutation was associated with acquisition of an AGAP3-BRAF fusion gene. Expression of the AGAP3-BRAF fusion in BRAF^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 AGAP3-BRAF fusion gene. Mixing experiments suggest that cells harboring both BRAF^V600E and AGAP3-BRAF only have a fitness advantage over parental BRAF^V600E cells during active treatment with a BRAF inhibitor.Conclusions: We report acquisition of a BRAF fusion as a novel mechanism of acquired resistance to vemurafenib in a patient with melanoma harboring a BRAF^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. Clin Cancer Res; 23(18); 5631-8. ©2017 AACR.

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