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|Ref Type||Journal Article|
|Authors||Caeser R, Collord G, Yao WQ, Chen Z, Vassiliou GS, Beer PA, Du MQ, Scott MA, Follows GA, Hodson DJ|
|Title||Targeting MEK in vemurafenib-resistant hairy cell leukemia.|
|Date||2018 Oct 19|
|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||F53C||missense||gain of function - predicted||MAP2K1 F53C does not lie within any known functional domains of the Map2k1 protein (UniProt.org). F53C results in increased Erk1/2 phosphorylation in vitro and has been associated with resistance to BRAF inhibitors (PMID: 30341394), and therefore, is predicted to result in a gain of Map2k1 protein function.||Y|
|MAP2K1||K57T||missense||gain of function - predicted||MAP2K1 K57T lies within the negative regulatory region of the Map2k1 protein (PMID: 24241536). K57T results in increased Erk1/2 phosphorylation in culture (PMID: 30341394), and has been demonstrated to occur as a secondary drug resistance mutation (PMID: 26644315, PMID: 28819429, PMID: 30341394), and therefore, is predicted to result in a gain of Map2k1 protein function.||Y|
|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 single patient with hairy cell leukemia who relapsed after initial response to Zelboraf (vemurafenib) was found to have acquired multiple clones with Mek/Erk activating mutations, of which the MAP2K1 K57T clone became dominant, and 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|