Reference Detail

Ref Type

Journal Article

PMID

(24448821)

Authors

Narita Y, Okamoto K, Kawada MI, Takase K, Minoshima Y, Kodama K, Iwata M, Miyamoto N, Sawada K

Title

Novel ATP-competitive MEK inhibitor E6201 is effective against vemurafenib-resistant melanoma harboring the MEK1-C121S mutation in a preclinical model.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	13	4	2014 Apr	823-32	Mol Cancer Ther

URL

Abstract Text

Many clinical cases of acquired resistance to the BRAF inhibitor vemurafenib have recently been reported. One of the causes of this acquired resistance is the BRAF downstream kinase point mutation MEK1-C121S. This mutation confers resistance to not only vemurafenib, but also to the allosteric MEK inhibitor selumetinib (AZD6244). Here, we investigated the pharmacologic activities and effectiveness of the novel MEK inhibitor E6201 against BRAF (v-raf murine sarcoma viral oncogene homolog B1)-V600E mutant melanoma harboring the MEK1-C121S mutation. A cell-free assay confirmed that E6201 is an ATP-competitive MEK inhibitor, meaning it has a different binding mode with MEK compared with allosteric MEK inhibitors. E6201 is more effective against BRAF-V600E mutant melanoma compared with BRAF wild-type melanoma based on MEK inhibition. We found that the acquired MEK1-C121S mutation in BRAF-V600E mutant melanoma conferred resistance to both vemurafenib and selumetinib but not E6201. The effectiveness of E6201 in this preclinical study is a result of its binding with MEK1 far from the C121S point mutation so the mutation is unable to influence the MAPK pathway inhibitory activity. These results support further clinical investigation of E6201.

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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	C121S	missense	gain of function	MAP2K1 C121S lies within the protein kinase domain of the Map2k1 protein (UniProt.org). C121S confers a gain of function on the Map2k1 protein as demonstrated by increased Erk1/2 (PMID: 25899310) and Mek phosphorylation in culture and confers acquired resistance to Raf and Mek inhibitors (PMID: 21383288, PMID: 24448821, PMID: 29483135, PMID: 29753091).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E MAP2K1 C121S	melanoma	decreased response	Selumetinib	Preclinical	Actionable	In a preclinical study, melanoma cell lines harboring BRAF V600E mutation and overexpressing MAP2K1 C121S were less sensitive than those overexpressing wild-type MAP2K1 to Selumetinib (AZD6244)-induced inhibition of Mapk pathway activation and cell proliferation in culture (PMID: 24448821).	24448821
BRAF V600E MAP2K1 C121S	melanoma	sensitive	E6201	Preclinical	Actionable	In a preclinical study, E6201 inhibited Mapk pathway activation and proliferation of melanoma cell line harboring BRAF V600E mutation and overexpressing MAP2K1 C121S in culture (PMID: 24448821).	24448821
BRAF V600E MAP2K1 C121S	melanoma	resistant	Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 C121S conferred resistance to Zelboraf (vemurafenib) in melanoma cell lines harboring BRAF V600E, resulting in decreased sensitivity to Zelboraf (vemurafenib)-induced inhibition of MAPK pathway activation and cell proliferation in culture (PMID: 24448821).	24448821
BRAF V600E	melanoma	sensitive	E6201	Preclinical	Actionable	In a preclinical study, E6201 inhibited Mapk pathway activation and proliferation of melanoma cell lines harboring BRAF V600E mutation in culture (PMID: 24448821).	24448821