title: Trametinib after disease reactivation under dabrafenib in Erdheim-Chester disease with bothBRAFandKRASmutations.
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 otherBRAF-mutant malignancies imply the importance of therapeutic strategies beyond BRAF inhibition. We report a patient with ECD who carried theBRAFV600Emutation and developed treatment resistance under BRAF inhibition despite initial treatment response. Genetic analyses of a newly developing ECD lesion revealed a somaticKRASQ61Hmutation without the presence ofBRAFV600EAccordingly, 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.
authors.affiliation: Medical Outpatient Clinic, University Hospital Basel, Basel, Switzerland.
authors.forename: Thierry M
authors.initials: TM
authors.lastname: Nordmann
authors.affiliation: Positron Emission Tomography/Computed Tomography Center North-West-Switzerland, Clara Hospital, Basel, Switzerland.
authors.forename: Freimut D
authors.initials: FD
authors.lastname: Juengling
authors.affiliation: Immunodeficiency Clinic.
authors.forename: Mike
authors.initials: M
authors.lastname: Recher
authors.affiliation: Clinical and Translational Immunology, Medical Outpatient Clinic and Department of Biomedicine.
authors.forename: Christoph T
authors.initials: CT
authors.lastname: Berger
authors.affiliation: Plastic, Reconstructive and Aesthetic Surgery, and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kalbermatten
authors.affiliation: Division of Oncology and Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wicki
authors.affiliation: Institute of Pathology, Cantonal Hospital Baselland, Liestal, Switzerland; and.
authors.forename: Aino
authors.initials: A
authors.lastname: Paasinen-Sohns
authors.affiliation: Institute of Pathology, Cantonal Hospital Baselland, Liestal, Switzerland; and.
authors.forename: Gieri
authors.initials: G
authors.lastname: Cathomas
authors.affiliation: Institute of Pathology, and.
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: Rheumatology, University Hospital Basel, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Daikeler
mesh_terms: D004351:Drug Resistance / Q000187:drug effects; D031249:Erdheim-Chester Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D010091:Oximes / Q000627:therapeutic use*; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011728:Pyridones / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000627:therapeutic use*
chemical_list: D007093:Imidazoles; C117307:KRAS protein, human; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); C561627:dabrafenib