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
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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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

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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	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	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

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