Drug-resistant BRAF V600E-mutant recurrent pleomorphic xanthoastrocytoma, CNS WHO Grade 3 successfully resolved with incidental discontinuation of combined BRAF and MEK inhibitor therapy.

Abstract

Background: Combination therapy with BRAF and MEK inhibitor holds promise for treating gliomas harboring the BRAF V600E mutation; however, the development of acquired resistance remains a challenge.

Case description: We describe a case of repeated recurrent BRAF-mutant pleomorphic xanthoastrocytoma (central nervous system World Health Organization grade 3) treated with combination therapy with BRAF and MEK inhibitor. The patient received dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor); however, she developed resistance to the combination therapy. Remarkably, incidental drug discontinuation contributed to the disappearance of the resistant tumor. The same phenomenon was repeatedly observed after that. Genetic analysis demonstrated that the resistant tumor had BRAF V600E amplification; the resistant tumor remained BRAF→MEK→ERK pathway dependent, and drug resistance might be due to elevated BRAF V600E expression. We speculated that ERK1/2 signal extremes caused by the discontinuation of the combination therapy affected the resistant tumor survival.

Conclusion: This case study provides important insights into novel treatment strategies and their underlying mechanisms for gliomas with BRAF mutations.