BRAF fusion as a novel mechanism of acquired resistance to vemurafenib in BRAF V600E mutant melanoma.

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. &nbsp;<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

Cancer Institute of New Jersey, Cancer Institute of New Jersey., Rutgers Cancer Institute of New Jersey., Radiation Oncology, Rutgers Cancer Institute of New Jersey., Medicine, Medical Oncology, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School., Chemical Biology, Rutgers, State University of New Jersey., Department of Medicine, Rutgers, The State University of New Jersey, Rutgers Cancer Institute of New Jersey., Cancer Institute of New Jersey, Rutgers Cancer Institute of New Jersey., Radiology, Rutgers Cancer Institute of New Jersey., Foundation Medicine, Inc., Central Comprehensive Cancer Centre., Molecular Biology and Biochemistry, Rutgers Cancer Institute of New Jersey., Gynecologic Oncology and Precision Medicine, Rutgers Cancer Institute of New Jersey., Medicine, Rutgers Cancer Institute of New Jersey., Medicine, Rutgers Cancer Institute of New Jersey This email address is being protected from spambots. You need JavaScript enabled to view it..