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Updated: Feb 10, 2026

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Clinical resistance associated with a novel MAP2K1 mutation in a patient with Langerhans cell histiocytosis
David O Azorsa1,2, David W Lee1,2, Daniel H Wai1,2
1Institute of Molecular Medicine, Phoenix Children's Hospital, Phoenix, Arizona.
Abstract:
Patients with Langerhans cell histiocytosis (LCH) harbor BRAF V600E and activating mutations of MAP2K1/MEK1 in 50% and 25% of cases, respectively. We evaluated a patient with treatment-refractory LCH for mutations in the RAS-RAF-MEK-ERK pathway and identified a novel mutation in the MAP2K1 gene resulting in a p.L98_K104 > Q deletion and predicted to be auto-activating. During treatment with the MEK inhibitor trametinib, the patient's disease showed significant progression. In vitro characterization of the MAP2K1 p.L98_K104 > Q deletion confirmed its effect on cellular activation of the ERK pathway and drug resistance.
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