Reference Detail

Ref Type

Journal Article

PMID

(25351745)

Authors

Arcila ME, Drilon A, Sylvester BE, Lovly CM, Borsu L, Reva B, Kris MG, Solit DB, Ladanyi M

Title

MAP2K1 (MEK1) Mutations Define a Distinct Subset of Lung Adenocarcinoma Associated with Smoking.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	21	8	2015 Apr 15	1935-43	Clin Cancer Res

URL

Abstract Text

Genetic alterations affecting the MAPK/ERK pathway are common in lung adenocarcinoma (LAD). Early steps of the signaling pathway are most often affected with EGFR, KRAS, and BRAF mutations encompassing more than 70% of all alterations. Somatic mutations in MEK1, located downstream of BRAF, are rare and remain poorly defined as a distinct molecular subset.Tumors harboring MEK1 mutations were identified through targeted screening of a large LAD cohort concurrently interrogated for recurrent mutations in MEK1, EGFR, KRAS, BRAF, ERBB2/HER2, NRAS, PIK3CA, and AKT. Additional cases were identified through a search of publically available cancer genomic datasets. Mutations were correlated with patient characteristics and treatment outcomes. Overall survival was compared with stage-matched patients with KRAS- and EGFR-mutant LADs.We identified 36 MEK1-mutated cases among 6,024 LAD (0.6%; 95% confidence interval, 0.42-0.85). The majority of patients were smokers (97%, n = 35/36). There was no association with age, sex, race, or stage. The most common mutations were K57N (64%, 23/36) followed by Q56P (19%, 7/36), all mutually exclusive with other driver mutations in the targeted panel. Transversions G:C>T:A were predominant (89%, 31/35), in keeping with smoking-associated DNA damage. Additional less common somatic mutations were identified in the kinase domain, all of which are predicted to converge into a single interaction area based on in silico 3D modeling.MEK1 mutations define a distinct subset of lung cancers (∼1%) with potential sensitivity to MEK inhibitors. Mutations are predominantly transversions, in keeping with a strong association with smoking.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
MAP2K1	NCBI	CFC3\|MAPKK1\|MEK1\|MEL\|MKK1\|PRKMK1		MAP2K1 (MEK1), mitogen-activated protein kinase kinase 1, is a serine-threonine kinase, which activates the RAS-RAF-MEK-ERK pathway in cell proliferation and differentiation (PMID: 22753777). MAP2K1 (MEK1) activating mutations have been identified in a number of solid tumor types including, melanoma (PMID: 29753091), colorectal (PMID: 28819429), lung adenocarcinoma (PMID: 25351745, PMID: 32361034), histiocytic sarcoma (PMID: 29768143), and Map2k1 mutations are often associated with resistance to Mek and Raf inhibition (PMID: 29753091).	Oncogene

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	D67N	missense	gain of function	MAP2K1 D67N does not lie within any known functional domains of the Map2k1 protein (UniProt.org). D67N confers a gain of function to Map2k1 as demonstrated by increased Erk activation (PMID: 25049390, PMID: 29483135), increased Rsk phosphorylation (PMID: 25351745), and transformation in culture (PMID: 25351745, PMID: 36442478), and is associated with BRAF inhibitor resistance in the context of BRAF V600E in culture (PMID: 28986383).	Y
MAP2K1	F53L	missense	gain of function	MAP2K1 F53L lies within the negative regulatory region of the Map2k1 protein (PMID: 24241536). F53L results in activation of Map2k1 as indicated by increased Erk and Mek phosphorylation (PMID: 25164765, PMID: 29483135), increased Rsk phosphorylation (PMID: 25351745), transformation activity in culture (PMID: 25351745, PMID: 36442478), and increased proliferation in a competition assay (PMID: 36442478), and demonstrates resistance to some Mek and Braf inhibitors (PMID: 29753091, PMID: 36442478).	Y
MAP2K1	K57N	missense	gain of function	MAP2K1 K57N lies within the negative regulatory region of the Map2k1 protein (PMID: 24241536). K57N confers a gain of function to Map2k1 as demonstrated by increased autophosphorylation (PMID: 29753091) and Erk phosphorylation (PMID: 18632602, PMID: 29753091), increased cell proliferation and cell viability in two different cell lines (PMID: 29533785, PMID: 18632602), transformation of cultured cells (PMID: 25351745, PMID: 36442478), increased proliferation in a competition assay (PMID: 36442478), and demonstrates resistance to some Mek and Braf inhibitors (PMID: 29753091, PMID: 36442478).	Y
MAP2K1	Q56P	missense	gain of function	MAP2K1 Q56P does not lie within any known functional domains of the Map2k1 protein (UniProt.org). Q56P confers a gain of function to the Map2k1 protein as indicated by increased kinase activity and the ability to transform cultured cells (PMID: 7651428, PMID: 22327936, PMID: 25351745) and increased proliferation in a competition assay (PMID: 36442478), and demonstrates resistance to some Mek and Braf inhibitors (PMID: 29753091).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
MAP2K1 F53L	Advanced Solid Tumor	sensitive	Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Koselugo (selumetinib) inhibited colony formation of transformed cells expressing MAP2K1 F53L in culture (PMID: 25351745).	25351745
MAP2K1 D67N	Advanced Solid Tumor	sensitive	Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Koselugo (selumetinib) inhibited colony formation of transformed cells expressing MAP2K1 D67N in culture (PMID: 25351745).	25351745
MAP2K1 K57N	Advanced Solid Tumor	sensitive	Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Koselugo (selumetinib) inhibited colony formation of transformed cells expressing MAP2K1 K57N in culture (PMID: 25351745).	25351745
MAP2K1 Q56P	Advanced Solid Tumor	sensitive	Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Koselugo (selumetinib) inhibited colony formation of transformed cells expressing MAP2K1 Q56P in culture (PMID: 25351745).	25351745