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Ref Type Journal Article
PMID (29768711)
Authors Azorsa DO, Lee DW, Wai DH, Bista R, Patel AR, Aleem E, Henry MM, Arceci RJ
Title Clinical resistance associated with a novel MAP2K1 mutation in a patient with Langerhans cell histiocytosis.
Journal Pediatric blood & cancer
Vol
Issue
Date 2018 May 16
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
MAP2K1 L98_K104delinsQ indel gain of function MAP2K1 L98_K104delinsQ results in the deletion of seven amino acids in the protein kinase domain of the Map2k1 protein from amino acids 98 to 104, combined with the insertion of a glutamine (Q) at the same site (UniProt.org). L98_K104delinsQ results in increased activation of Map2k1 and elevated phosphorylation of Erk and Akt in culture (PMID: 29768711), and has been demonstrated to confer resistance to Mek inhibitors (PMID: 29768711). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MAP2K1 L98_K104delinsQ Advanced Solid Tumor resistant SCH772984 Preclinical - Cell culture Actionable In a preclinical study, SCH772984 treatment failed to inhibit activation of Mek and Erk in human cells expressing MAP2K1 L98_K104delinsQ in culture (PMID: 29768711). 29768711
MAP2K1 L98_K104delinsQ Advanced Solid Tumor resistant Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) treatment failed to inhibit activation of Mek and Erk in human cells expressing MAP2K1 L98_K104delinsQ in culture (PMID: 29768711). 29768711
MAP2K1 L98_K104delinsQ Advanced Solid Tumor resistant U0126 Preclinical - Cell culture Actionable In a preclinical study, U0126 treatment failed to inhibit activation of Mek and Erk in human cells expressing MAP2K1 L98_K104delinsQ in culture (PMID: 29768711). 29768711
MAP2K1 L98_K104delinsQ Advanced Solid Tumor resistant MK2206 Preclinical - Cell culture Actionable In a preclinical study, MK2206 treatment failed to inhibit activation of Mek and Erk in human cells expressing MAP2K1 L98_K104delinsQ in culture (PMID: 29768711). 29768711
MAP2K1 L98_K104delinsQ lymphatic system cancer predicted - resistant Trametinib Case Reports/Case Series Actionable In a clinical case study, a patient with Langerhans cell histiocytosis harboring MAP2K1 L98_K104delinsQ demonstrated progressive disease when treated with Mekinist (trametinib) (PMID: 29768711). 29768711