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Ref Type Journal Article
PMID (19915144)
Authors Emery CM, Vijayendran KG, Zipser MC, Sawyer AM, Niu L, Kim JJ, Hatton C, Chopra R, Oberholzer PA, Karpova MB, MacConaill LE, Zhang J, Gray NS, Sellers WR, Dummer R, Garraway LA
Title MEK1 mutations confer resistance to MEK and B-RAF inhibition.
Journal Proceedings of the National Academy of Sciences of the United States of America
Vol 106
Issue 48
Date 2009 Dec 1
URL
Abstract Text Genetic alterations that activate the mitogen-activated protein kinase (MAP kinase) pathway occur commonly in cancer. For example, the majority of melanomas harbor mutations in the BRAF oncogene, which are predicted to confer enhanced sensitivity to pharmacologic MAP kinase inhibition (e.g., RAF or MEK inhibitors). We investigated the clinical relevance of MEK dependency in melanoma by massively parallel sequencing of resistant clones generated from a MEK1 random mutagenesis screen in vitro, as well as tumors obtained from relapsed patients following treatment with AZD6244, an allosteric MEK inhibitor. Most mutations conferring resistance to MEK inhibition in vitro populated the allosteric drug binding pocket or alpha-helix C and showed robust ( approximately 100-fold) resistance to allosteric MEK inhibition. Other mutations affected MEK1 codons located within or abutting the N-terminal negative regulatory helix (helix A), which also undergo gain-of-function germline mutations in cardio-facio-cutaneous (CFC) syndrome. One such mutation, MEK1(P124L), was identified in a resistant metastatic focus that emerged in a melanoma patient treated with AZD6244. Both MEK1(P124L) and MEK1(Q56P), which disrupts helix A, conferred cross-resistance to PLX4720, a selective B-RAF inhibitor. However, exposing BRAF-mutant melanoma cells to AZD6244 and PLX4720 in combination prevented emergence of resistant clones. These results affirm the importance of MEK dependency in BRAF-mutant melanoma and suggest novel mechanisms of resistance to MEK and B-RAF inhibitors that may have important clinical implications.

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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 H119P missense unknown MAP2K1 H119P lies within the protein kinase domain of the Map2k1 protein (UniProt.org). H119P has been described as a drug resistance mutation (PMID: 19915144), but has not been biochemically characterized and therefore, its effect on Map2k1 protein function is unknown (PubMed, Aug 2020). Y
MAP2K1 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
MAP2K1 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
MAP2K1 L115R missense unknown MAP2K1 L115R lies within the protein kinase domain of the Map2k1 protein (UniProt.org). L115R has been described as a drug resistance mutation (PMID: 19915144), but has not been biochemically characterized and therefore, its effect on Map2k1 protein function is unknown (PubMed, Aug 2020). Y
MAP2K1 P124L missense gain of function MAP2K1 P124L lies within the protein kinase domain of the Map2k1 protein (UniProt.org). P124L confers a gain of function on the Map2k1 protein as demonstrated by increased Erk 1/2 phosphorylation (PMID: 19915144, PMID: 29483135) and Mek phosphorylation in cultured cells (PMID: 29483135) and also confers resistance to some Mek and Braf inhibitors in melanoma cells (PMID: 19915144). Y
MAP2K1 P124S missense unknown MAP2K1 P124S lies within the protein kinase domain of the Map2k1 protein (UniProt.org). The functional effect of P124S is conflicting, as it has been reported to confer a gain of function on the Map2k1 protein as demonstrated by increased ERK1/2 phosphorylation, but has similar induction of cell proliferation and viability levels as wild-type Map2k1 (PMID: 29533785), and confers resistance to Mek and Braf inhibitors in melanoma cells (PMID: 19915144, PMID: 22197931). Y
MAP2K1 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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E MAP2K1 H119P melanoma resistant Selumetinib Preclinical Actionable In a preclinical study, melanoma cells harboring BRAF V600E treated with Selumetinib (AZD6244) in culture demonstrated resistance, which was a result of the resistance mutation, MAP2K1 H119P (PMID: 19915144). 19915144
BRAF V600E MAP2K1 Q56P melanoma resistant PLX4720 Preclinical Actionable In a preclinical study, melanoma cells harboring the MAP2K1 Q56P mutation in the presence of BRAF V600E were resistant to the B-RAF inhibitor PLX4720 in culture (PMID: 19915144). 19915144
MAP2K1 L115P melanoma resistant Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Selumetinib (AZD6244) did not inhibit proliferation of melanoma cells expressing Map2k1 L115P (PMID: 19915144). 19915144
MAP2K1 P124L melanoma resistant Selumetinib Preclinical Actionable In a preclinical study, transformed human melanoma cells expressing MAP2K1 P124L demonstrated resistance to the MEK inhibitor, Selumetinib (AZD6244) (PMID: 19915144). 19915144
MAP2K1 L115P melanoma resistant CI-1040 Preclinical - Cell culture Actionable In a preclinical study, CI-1040 (PD184352) did not inhibit proliferation of melanoma cells expressing Map2k1 L115P (PMID: 19915144). 19915144
MAP2K1 I103N melanoma resistant Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Selumetinib (AZD6244) did not inhibit proliferation of melanoma cells expressing Map2k1 I103N (PMID: 19915144). 19915144
BRAF V600E MAP2K1 V211D melanoma resistant Selumetinib Preclinical Actionable In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K V211D demonstrated resistance to growth inhibition by Selumetinib (AZD6244) in cell culture (PMID: 19915144). 19915144
BRAF V600E MAP2K1 Q56P melanoma resistant Selumetinib Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring the MAP2K1 Q56P mutation in the presence of BRAF V600E were resistant to the MEK inhibitor, Koselugo (selumetinib), in cell culture (PMID: 19915144). 19915144
BRAF V600E MAP2K1 Q56P melanoma sensitive PLX4720 + Selumetinib Preclinical Actionable In a preclinical study, combined treatment with selumetinib and PLX4720 strongly suppressed the emergence of resistant MAP2K1 mutations in BRAF V600E cells in culture (PMID: 19915144). 19915144
BRAF V600E MAP2K1 V211D melanoma resistant CI-1040 Preclinical Actionable In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K V211D demonstrated resistance to growth inhibition by CI-1040 in cell culture (PMID: 19915144). 19915144
MAP2K1 I103N melanoma resistant CI-1040 Preclinical - Cell culture Actionable In a preclinical study, CI-1040 (PD184352) did not inhibit proliferation of melanoma cells expressing Map2k1 I103N (PMID: 19915144). 19915144