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Trametinib after disease reactivation under dabrafenib in Erdheim-Chester disease with both BRAF and KRAS mutations
Journal
Blood
Volume
129
Number
7
Pages / Article-Number
879-882
Mesh terms
Drug Resistance, drug effects; Erdheim-Chester Disease, pathology; Female; Humans; Imidazoles, therapeutic use; Middle Aged; Mitogen-Activated Protein Kinase Kinases, antagonists & inhibitors; Oximes, therapeutic use; Point Mutation; Protein Kinase Inhibitors, therapeutic use; Proto-Oncogene Proteins B-raf, genetics; Proto-Oncogene Proteins p21(ras), genetics; Pyridones, therapeutic use; Pyrimidinones, therapeutic use
Abstract
Major advances have been made in understanding the pathogenesis of Erdheim-Chester disease (ECD) leading to novel treatment strategies. Targeted therapies such as BRAF inhibition have shown a significant impact on disease management, emphasizing the importance of the activated mitogen-associated protein kinase pathway in this disease. However, incomplete responsiveness, potentially limiting adverse effects, and the occurrence of treatment resistance to BRAF inhibition observed in other BRAF-mutant malignancies imply the importance of therapeutic strategies beyond BRAF inhibition. We report a patient with ECD who carried the BRAFV600E mutation and developed treatment resistance under BRAF inhibition despite initial treatment response. Genetic analyses of a newly developing ECD lesion revealed a somatic KRASQ61H mutation without the presence of BRAFV600E Accordingly, the addition of MEK-inhibiting trametinib to BRAF-inhibiting dabrafenib was able to overcome acquired partial treatment resistance. This is the first report of treatment resistance as a result of a secondary MAPK pathway-activating mutation during BRAF inhibition in ECD. This case contributes to the ongoing efforts of simultaneous BRAF/MEK inhibition as a promising strategy in ECD.
