Reference Detail

Ref Type Journal Article
PMID (29753091)
Authors Kinoshita-Kikuta E, Kinoshita E, Ueda S, Ino Y, Kimura Y, Hirano H, Koike T
Title Increase in constitutively active MEK1 species by introduction of MEK1 mutations identified in cancers.
Journal Biochimica et biophysica acta
Vol
Issue
Date 2018 May 09
URL
Abstract Text The kinase MEK1 is an essential component of the mitogen-activated protein kinase cascades. Somatic mutations that have been identified in the MEK1-coding gene generally enhance kinase activity. Consequently, MEK1 has attracted much interest as a target for cancer therapy to block the aberrant activity. By using Phos-tag affinity electrophoresis, we found that the introduction of mutations detected in certain sporadic cancers or in MEK-inhibitor-resistant cancer cells produced constitutively active MEK1 species containing phosphorylated Ser-218 and Ser-222 residues; it also enhanced the constitutive activity of the kinase. Phosphorylation profiling of the mutants in the presence of inhibitors of RAF/MEK demonstrated that several mutations conferred resistance to multiple inhibitors as a result of an increase in the quantity of active MEK1 species containing the two phosphorylated Ser-218 and Ser-222 residues. Phos-tag-based phosphorylation profiling of MEK1 can therefore provide clinical insights into characteristics of individual mutations in the MEK1-coding gene.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
MAP2K1 NCBI CFC3|MAPKK1|MEK1|MKK1|PRKMK1 MAP2K1 (MEK1), mitogen-activated protein kinase kinase 1, is a serine-threonine kinase, which activates that 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), histiocytic sarcoma (PMID: 29768143), and Map2k1 mutations are often associated with resistance to Mek and Raf inhibition (PMID: 29753091). not a driver
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
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 has been demonstrated to confer acquired resistance to Raf and Mek inhibitors (PMID: 21383288, PMID: 24448821, PMID: 29483135, PMID: 29753091). Y
E203K missense gain of function MAP2K1 E203K lies within the protein kinase domain of the Map2k1 protein (UniProt.org). E203K results in constitutive phosphorylation of Erk, is transforming in cell culture (PMID: 22197931, PMID: 29483135), and increases autophosphorylation of Map2k1 (PMID: 29753091). Y
E203Q missense no effect MAP2K1 E203Q lies within the protein kinase domain of the Map2k1 protein (UniProt.org). E203Q has been demonstrated to have autohphosphorylation and kinase activities similar to wild-type Map2k1 in in vitro assays (PMID: 29753091).
F129L missense gain of function MAP2K1 F129L lies within the protein kinase domain of the Map2k1 protein (UniProt.org). F129L confers a gain of function to the Map2k1 protein as demonstrated by increased kinase activity compared to wild-type, activation of downstream Erk signaling, and increased binding affinity to c-Raf (PMID: 21705440) and also demonstrates resistance to some Mek and Braf inhibitors (PMID: 29753091). Y
F53L missense gain of function MAP2K1 F53L does not lie within any known functional domains of the Map2k1 protein (UniProt.org). F53L results in activation of Map2k1 as indicated by increased Erk and Mek phosphorylation in cell culture (PMID: 25164765, PMID: 29483135) and also demonstrates resistance to some Mek and Braf inhibitors (PMID: 29753091). Y
F53S missense unknown MAP2K1 F53S does not lie within any known functional domains of the Map2k1 protein (UniProt.org). The functional effect of F53S is conflicting, as it has been reported to confer a gain of function to the Map2k1 protein as indicated by Erk phosphorylation greater than that induced by wild-type, but not as active as other constitutively active Map2k1 mutants in culture (PMID: 16439621, PMID: 12370306) and in another study, F53S had autophosphorylation levels similar to wild-type Map2k1 (PMID: 29753091).
G128N missense no effect - predicted MAP2K1 G128N lies within the protein kinase domain of the Map2k1 protein (UniProt.org). G128N has been demonstrated to have autophosphorylation levels similar to wild-type Map2k1 in an in-vitro assay (PMID: 29753091) and therefore, is predicted to have no effect on Map2k1 protein function.
G128V missense no effect - predicted MAP2K1 G128V lies within the protein kinase domain of the Map2k1 protein (UniProt.org). G128V has been demonstrated to have autophosphorylation levels similar to wild-type Map2k1 in an in vitro assay (PMID: 29753091) and has also been described as a drug resistance mutation (PMID: 24265153). Y
I103N missense gain of function - predicted MAP2K1 I103N lies within the protein kinase domain of the Map2k1 protein (UniProt.org). I103N is predicted to confer a gain of function on the Map2k1 protein as demonstrated by increased Map2k1 autophosphorylation in cell culture (PMID: 29753091) and is also associated with resistance to Mek inhibitors (PMID: 12370306, PMID: 19915144). Y
I111S missense gain of function MAP2K1 I111S lies within the protein kinase domain of the Map2k1 protein (UniProt.org). I111S confers a gain of function on the Map2k1 protein as demonstrated by increased autophosphorylation and Erk phosphorylation and also demonstrates resistance to some Mek and Braf inhibitors (PMID: 29753091). Y
K57N missense gain of function MAP2K1 K57N does not lie within any known functional domains of the Map2k1 protein (UniProt.org). K57N confers a gain of function on the Map2k1 protein as demonstrated by increased autophosphorylation (PMID: 29753091), increased Erk phosphorylation (PMID: 18632602, PMID: 29753091), increased cell proliferation and cell viability as compared to wild-type Map2k1, in two different cell lines (PMID: 29533785, PMID: 18632602), and also demonstrates resistance to some Mek and Braf inhibitors (PMID: 29753091). Y
K59del deletion unknown MAP2K1 K59del results in the deletion of an amino acid in the protein kinase domain of the Map2k1 protein at amino acid 59 (UniProt.org). The functional effect of K59del is conflicting as K59del results in increased Mek and Erk phosphorylation in culture (PMID: 22389471), but demonstrates autophosphorylation levels similar to wild-type Map2k1 in another study (PMID: 29753091), and therefore, its effect on Map2k1 protein function is unknown.
L115P missense gain of function MAP2K1 L115P lies within the protein kinase domain of the Map2k1 protein (UniProt.org). L115P confers a gain of function on the kinase activity of the Map2k1 protein, as demonstrated by increased autophosphorylation (PMID: 29753091) and increased basal kinase activity (PMID: 12370306), and is also associated with decreased binding and resistance to Mek inhibitors (PMID: 12370306, PMID: 19915144, PMID: 26399658). Y
L42F missense no effect MAP2K1 L42F does not lie within any known functional domains of the Map2k1 protein (UniProt.org). L42F has been demonstrated to have autohphosphorylation and kinase activities similar to wild-type Map2k1 in in vitro assays (PMID: 29753091).
P124Q missense unknown MAP2K1 P124Q lies within the protein kinase domain of the Map2k1 protein (UniProt.org). The functional effect of P124Q is conflicting as P124Q results in increased Erk1/2 phosphorylation in culture, and is associated with resistance to a Raf inhibitor (PMID: 25370473), but demonstrates autophosphorylation and kinase activity similar to wild-type Map2k1 in another study (PMID: 29753091), and therefore, its effect on Map2k1 protein function is unknown. Y
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: 22327936, PMID: 7651428) and also demonstrates resistance to some Mek and Braf inhibitors (PMID: 29753091). Y
T55P missense no effect - predicted MAP2K1 T55P does not lie within any known functional domains of the Map2k1 protein (UniProt.org). T55P has been demonstrated to have autophosphorylation levels similar to wild-type Map2k1 in an in vitro assay (PMID: 29753091) and therefore, is predicted to have no effect on Map2k1 protein function.
V211D missense gain of function MAP2K1 V211D lies within the protein kinase domain of the Map2k1 protein (UniProt.org). V211D confers a gain of function to Map2k1, as demonstrated by increased phosphorylation of Mek and Erk in cultured cells and in vitro kinase assays, and also demonstrates Braf and Mek inhibitor resistance (PMID: 29753091, PMID: 19915144, PMID: 31227518). Y
Y130C missense unknown MAP2K1 Y130C lies within the protein kinase domain of the Map2k1 protein (UniProt.org). The functional effect of Y130C is conflicting, as it has been reported to confer a gain of function to the Map2k1 protein function as indicated by increased Erk phosphorylation in cell culture (PMID: 16439621), however, in another study, Y130C had autohphosphorylation levels similar to wild-type Map2k1 in an in vitro assay (PMID: 29753091).
Y130H missense no effect - predicted MAP2K1 Y130H lies within the protein kinase domain of the Map2k1 protein (UniProt.org). Y130H has been demonstrated to have autohphosphorylation levels similar to wild-type Map2k1 in an in-vitro assay (PMID: 29753091) and therefore, is predicted to have no effect on Map2k1 protein function.
Y130N missense no effect - predicted MAP2K1 Y130N lies within the protein kinase domain of the Map2k1 protein (UniProt.org). Y130N has been demonstrated to have autohphosphorylation levels similar to wild-type Map2k1 in an in-vitro assay (PMID: 29753091) and therefore, is predicted to have no effect on Map2k1 protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MAP2K1 Q56P Advanced Solid Tumor resistant GDC0879 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 Q56P displayed resistance to the Braf inhibitor, GDC-0879, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 Q56P Advanced Solid Tumor sensitive Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Map2k1 Q56P displayed sensitivity to the Mek inhibitor, Selumetinib (AZD6244), as demonstrated by reversal of active Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 V211D Advanced Solid Tumor sensitive PLX4720 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 V211D displayed sensitivity to the Braf inhibitor, PLX4720, as demonstrated by reversal of active Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 F129L Advanced Solid Tumor resistant GDC0879 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 F129L displayed resistance to the Braf inhibitor, GDC-0879, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 C121S Advanced Solid Tumor resistant AZD8330 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 C121S displayed resistance to the Mek inhibitor, AZD8330, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 F53L Advanced Solid Tumor resistant PD98059 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 F53L displayed resistance to the Mek inhibitor, PD98059, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 I111S Advanced Solid Tumor resistant GDC0879 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 I111S displayed resistance to the Braf inhibitor, GDC-0879, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 F53L Advanced Solid Tumor resistant GDC0879 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 F53L displayed resistance to the Braf inhibitor, GDC-0879, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 C121S Advanced Solid Tumor resistant GDC0879 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 C121S displayed resistance to the Braf inhibitor, GDC-0879, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 F53L Advanced Solid Tumor resistant Regorafenib Preclinical - Cell culture Actionable In a preclinical study, Map2k1 F53L displayed resistance to Stivarga (regorafenib; BAY 73-4506), as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 K57N Advanced Solid Tumor resistant GDC0879 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 K57N displayed resistance to the Braf inhibitor, GDC-0879, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 Q56P Advanced Solid Tumor resistant Regorafenib Preclinical - Cell culture Actionable In a preclinical study, Map2k1 Q56P displayed resistance to Stivarga (regorafenib; BAY 73-4506), as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 C121S Advanced Solid Tumor sensitive Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Map2k1 C121S displayed sensitivity to the Mek inhibitor, Selumetinib (AZD6244), as demonstrated by reversal of active Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 Q56P Advanced Solid Tumor resistant PD98059 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 Q56P displayed resistance to the Mek inhibitor, PD98059, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 Q56P Advanced Solid Tumor sensitive PLX4720 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 Q56P displayed sensitivity to the Braf inhibitor, PLX4720, as demonstrated by reversal of active Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 V211D Advanced Solid Tumor resistant AZD8330 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 V211D displayed resistance to the Mek inhibitor, AZD8330, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 K57N Advanced Solid Tumor sensitive Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Map2k1 K57N displayed sensitivity to the Mek inhibitor, Selumetinib (AZD6244), as demonstrated by reversal of active Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 I111S Advanced Solid Tumor resistant AZD8330 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 I111S displayed resistance to the Mek inhibitor, AZD8330, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 I111S Advanced Solid Tumor resistant PD98059 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 I111S displayed resistance to the Mek inhibitor, PD98059, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 K57N Advanced Solid Tumor sensitive PLX4720 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 K57N displayed sensitivity to the Braf inhibitor, PLX4720, as demonstrated by reversal of active Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 K57N Advanced Solid Tumor resistant PD98059 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 K57N displayed resistance to the Mek inhibitor, PD98059, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 C121S Advanced Solid Tumor sensitive PLX4720 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 C121S displayed sensitivity to the Braf inhibitor, PLX4720, as demonstrated by reversal of active Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 C121S Advanced Solid Tumor resistant PD98059 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 C121S displayed resistance to the Mek inhibitor, PD98059, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 F129L Advanced Solid Tumor resistant PD98059 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 F129L displayed resistance to the Mek inhibitor, PD98059, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 I111S Advanced Solid Tumor resistant Regorafenib Preclinical - Cell culture Actionable In a preclinical study, Map2k1 I111S displayed resistance to Stivarga (regorafenib; BAY 73-4506), as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 I111S Advanced Solid Tumor sensitive Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Map2k1 I111S displayed sensitivity to the Mek inhibitor, Selumetinib (AZD6244), as demonstrated by reversal of active Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 I111S Advanced Solid Tumor sensitive PLX4720 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 I111S displayed sensitivity to the Braf inhibitor, PLX4720, as demonstrated by reversal of active Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 C121S Advanced Solid Tumor resistant Regorafenib Preclinical - Cell culture Actionable In a preclinical study, Map2k1 C121S displayed resistance to Stivarga (regorafenib; BAY 73-4506), as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 F129L Advanced Solid Tumor resistant AZD8330 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 F129L displayed resistance to the Mek inhibitor, AZD8330, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 V211D Advanced Solid Tumor resistant GDC0879 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 V211D displayed resistance to the Braf inhibitor, GDC-0879, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 F53L Advanced Solid Tumor sensitive Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Map2k1 F53L displayed sensitivity to the Mek inhibitor, Selumetinib (AZD6244), as demonstrated by reversal of active Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 Q56P Advanced Solid Tumor resistant AZD8330 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 Q56P displayed resistance to the Mek inhibitor, AZD8330, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 K57N Advanced Solid Tumor resistant AZD8330 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 K57N displayed resistance to the Mek inhibitor, AZD8330, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 F129L Advanced Solid Tumor sensitive Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Map2k1 F129L displayed sensitivity to the Mek inhibitor, Selumetinib (AZD6244), as demonstrated by reversal of active Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 F129L Advanced Solid Tumor resistant Regorafenib Preclinical - Cell culture Actionable In a preclinical study, Map2k1 F129L displayed resistance to Stivarga (regorafenib; BAY 73-4506), as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 V211D Advanced Solid Tumor resistant PD98059 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 V211D displayed resistance to the Mek inhibitor, PD98059, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 K57N Advanced Solid Tumor resistant Regorafenib Preclinical - Cell culture Actionable In a preclinical study, Map2k1 K57N displayed resistance to Stivarga (regorafenib; BAY 73-4506), as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 F53L Advanced Solid Tumor sensitive PLX4720 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 F53L displayed sensitivity to the Braf inhibitor, PLX4720, as demonstrated by reversal of active Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 V211D Advanced Solid Tumor resistant Regorafenib Preclinical - Cell culture Actionable In a preclinical study, Map2k1 V211D displayed resistance to Stivarga (regorafenib; BAY 73-4506), as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 V211D Advanced Solid Tumor resistant Selumetinib Preclinical Actionable In a preclinical study, Map2k1 V211D displayed resistance to the Mek inhibitor, Selumetinib (AZD6244), as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 F53L Advanced Solid Tumor resistant AZD8330 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 F53L displayed resistance to the Mek inhibitor, AZD8330, as demonstrated by constitutive activation of Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091
MAP2K1 F129L Advanced Solid Tumor sensitive PLX4720 Preclinical - Cell culture Actionable In a preclinical study, Map2k1 F129L displayed sensitivity to the Braf inhibitor, PLX4720, as demonstrated by reversal of active Map2k1 in transformed human kidney cells (PMID: 29753091). 29753091