Trametinib following disease reactivation under dabrafenib in Erdheim-Chester disease with both BRAF and KRAS mutations.

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 (MAPK) pathway in this disease. However, incomplete responsiveness, potentially limiting side 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 of a patient with ECD carrying the BRAF mutation developing treatment resistance under BRAF inhibition despite initial treatment response. Genetic analyses of a newly developing ECD lesion revealed a somatic KRAS mutation, without the presence of BRAF 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 due to 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.