Fusion as a Novel Mechanism of Acquired Resistance to Vemurafenib in Mutant Melanoma.

Many patients with 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. Comprehensive genomic profiling of serial biopsies was performed in a patient with a mutant metastatic melanoma who developed resistance to vemurafenib. An fusion gene, identified in the vemurafenib-resistant tumor, was expressed in melanoma cell lines, and its effect on drug sensitivity was evaluated. Clinical resistance to vemurafenib in a melanoma harboring a mutation was associated with acquisition of an fusion gene. Expression of the fusion in 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 fusion gene. Mixing experiments suggest that cells harboring both and only have a fitness advantage over parental cells during active treatment with a BRAF inhibitor. We report acquisition of a fusion as a novel mechanism of acquired resistance to vemurafenib in a patient with melanoma harboring a 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. .