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

Blood. 2017 Feb 16;129(7):879-882. doi: 10.1182/blood-2016-09-740217. Epub 2016 Dec 9.


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.

Publication types

  • Case Reports

MeSH terms

  • Drug Resistance / drug effects
  • Erdheim-Chester Disease / drug therapy*
  • Erdheim-Chester Disease / genetics
  • 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 / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Pyridones / therapeutic use*
  • Pyrimidinones / therapeutic use*


  • Imidazoles
  • KRAS protein, human
  • Oximes
  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidinones
  • trametinib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Mitogen-Activated Protein Kinase Kinases
  • Proto-Oncogene Proteins p21(ras)
  • dabrafenib