Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Pediatric blood & cancer			2018 May 16	e27237	Pediatr Blood Cancer

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	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	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
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	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