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Gene MAP2K1
Variant K57T
Impact List missense
Protein Effect gain of function
Gene Variant Descriptions MAP2K1 K57T lies within the negative regulatory region of the Map2k1 protein (PMID: 24241536). K57T confers a gain of function to Map2k1 as demonstrated by increased Erk1/2 phosphorylation (PMID: 30341394, PMID: 32641410) and transformation activity in cultured cells and increased proliferation in a competition assay (PMID: 36442478), and occurs as a secondary drug resistance mutation in the context of BRAF inhibitors (PMID: 26644315, PMID: 28819429, PMID: 30341394).
Associated Drug Resistance Y
Category Variants Paths

MAP2K1 mutant MAP2K1 act mut MAP2K1 K57T

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Transcript NM_002755.4
gDNA chr15:g.66435116A>C
cDNA c.170A>C
Protein p.K57T
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
XM_017022411.2 chr15:g.66435116A>C c.170A>C p.K57T RefSeq GRCh38/hg38
XM_017022411.3 chr15:g.66435116A>C c.170A>C p.K57T RefSeq GRCh38/hg38
XM_017022411 chr15:g.66435116A>C c.170A>C p.K57T RefSeq GRCh38/hg38
NM_002755.4 chr15:g.66435116A>C c.170A>C p.K57T RefSeq GRCh38/hg38
NM_002755 chr15:g.66435116A>C c.170A>C p.K57T RefSeq GRCh38/hg38
NM_002755.3 chr15:g.66435116A>C c.170A>C p.K57T RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E MAP2K1 K57T refractory hairy cell leukemia predicted - sensitive Cobimetinib + Vemurafenib Case Reports/Case Series Actionable In a clinical case study, a patient with hairy cell leukemia harboring BRAF V600E who relapsed after initial response to Zelboraf (vemurafenib) and was found to have acquired multiple clones with Mek/Erk activating mutations, including MAP2K1 K57T, demonstrated a sustained response greater than 12 months to combined Zelboraf (vemurafenib) and Cotellic (cobimetinib) treatment (PMID: 30341394). 30341394
BRAF V600E MAP2K1 K57T hairy cell leukemia predicted - resistant Vemurafenib Case Reports/Case Series Actionable In a clinical case study, a single patient with hairy cell leukemia harboring BRAF V600E, who relapsed after a 38 week remission in response to Zelboraf (vemurafenib) treatment, was found to have acquired multiple clones with Mek/Erk activating mutations, of which the MAP2K1 K57T clone became dominant (PMID: 30341394). 30341394
BRAF V600E MAP2K1 K57T melanoma resistant Cobimetinib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line harboring BRAF V600E and expressing MAP2K1 K57T was resistant to Cotellic (cobimetinib) in culture (PMID: 36442478). 36442478
BRAF V600E MAP2K1 K57T melanoma resistant Binimetinib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line harboring BRAF V600E and expressing MAP2K1 K57T was resistant to Mektovi (binimetinib) in culture (PMID: 36442478). 36442478
BRAF V600E MAP2K1 K57T melanoma resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line harboring BRAF V600E and expressing MAP2K1 K57T was resistant to Zelboraf (vemurafenib) in culture (PMID: 36442478). 36442478
BRAF V600E MAP2K1 K57T melanoma resistant Dabrafenib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line harboring BRAF V600E and expressing MAP2K1 K57T was resistant to Tafinlar (dabrafenib) in culture (PMID: 36442478). 36442478
BRAF V600E MAP2K1 K57T melanoma resistant Encorafenib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line harboring BRAF V600E and expressing MAP2K1 K57T was resistant to Braftovi (encorafenib) in culture (PMID: 36442478). 36442478
BRAF V600E MAP2K1 K57T melanoma sensitive Cobimetinib + Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, the combination of Zelboraf (vemurafenib) and Cotellic (cobimetinib) synergistically inhibited viability of a melanoma cell line harboring BRAF V600E and expressing MAP2K1 K57T in culture (PMID: 36442478). 36442478
BRAF V600E MAP2K1 K57T melanoma sensitive Dabrafenib + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) synergistically inhibited viability of a melanoma cell line harboring BRAF V600E and expressing MAP2K1 K57T in culture (PMID: 36442478). 36442478
BRAF V600E MAP2K1 K57T melanoma sensitive Binimetinib + Encorafenib Preclinical - Cell culture Actionable In a preclinical study, the combination of Braftovi (encorafenib) and Mektovi (binimetinib) synergistically inhibited viability of a melanoma cell line harboring BRAF V600E and expressing MAP2K1 K57T in culture (PMID: 36442478). 36442478
BRAF V600E MAP2K1 K57T colorectal cancer predicted - resistant Cetuximab + Fluorouracil + Leucovorin + Vemurafenib Case Reports/Case Series Actionable In a Phase II trial (MODUL), a patient with metastatic colorectal cancer harboring BRAF V600E was found to have acquired MAP2K1 K57T prior to progression on treatment with the combination of Zelboraf (vemurafenib), Erbitux (cetuximab), Adrucil (fluorouracil), and Wellcovorin (leucovorin) (PMID: 36921494; NCT02291289). 36921494