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. <br /><br />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.<br /><br />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 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 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.<br /><br />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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2017 May 24 [Epub ahead of print]
Atul Kulkarni, Husam Al-Hraishawi, Srilatha Simhadri, Kim M Hirshfield, Suzie Chen, Sharon R Pine, Chandrika Jeyamohan, Levi Sokol, Siraj M Ali, Man Lung Teo, Eileen White, Lorna Rodriguez-Rodriguez, Janice M Mehnert, Shridar Ganesan