BRAF fusion as a novel mechanism of acquired resistance to vemurafenib in BRAFV600E mutant melanoma

Atul Kulkarni, Husam Al-Hraishawi, Srilatha Simhadri, Kim M. Hirshfield, Suzie Chen, Sharon Pine, Chandrika Jeyamohan, Levi Sokol, Siraj Ali, Man Lung Teo, Eileen White, Lorna Rodriguez-Rodriguez, Janice M. Mehnert, Shridar Ganesan

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Purpose: Many patients with BRAFV600E 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 BRAFV600E mutant metastatic melanoma who developed resistance to vemurafenib. An AGAP3–BRAF fusion gene, identified in the vemurafenib-resistant tumor, was expressed in BRAFV600E melanoma cell lines, and its effect on drug sensitivity was evaluated. Results: Clinical resistance to vemurafenib in a melanoma harboring a BRAFV600E mutation was associated with acquisition of an AGAP3–BRAF fusion gene. Expression of the AGAP3–BRAF fusion in BRAFV600E 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 BRAFV600E and AGAP3–BRAF only have a fitness advantage over parental BRAFV600E 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 BRAFV600E 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.

Original languageEnglish (US)
Pages (from-to)5631-5638
Number of pages8
JournalClinical Cancer Research
Volume23
Issue number18
DOIs
StatePublished - Sep 15 2017

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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