Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Proceedings of the National Academy of Sciences of the United States of America	106	48	2009 Dec 1	20411-6	Proc Natl Acad Sci U S A

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, Mar 2024).	Y
MAP2K1	I103N	missense	gain of function	MAP2K1 I103N lies within the protein kinase domain of the Map2k1 protein (UniProt.org). I103N confers a gain of function to the Map2k1 protein as demonstrated by elevated basal kinase activity in an in vitro assay (PMID: 12370306), increased Map2k1 autophosphorylation (PMID: 29753091), and transformation activity in cell culture and increased proliferation in a competition assay (PMID: 36442478), and is also associated with resistance to Mek inhibitors (PMID: 12370306, PMID: 19915144).	Y
MAP2K1	I111N	missense	gain of function - predicted	MAP2K1 I111N lies within the protein kinase domain of the Map2k1 protein (UniProt.org). I111N is predicted to confer a gain of function to the Map2k1 protein as demonstrated by increased Mek and Erk phosphorylation in cultured cells (PMID: 19915144), and is also associated with resistance to Mek inhibitors (PMID: 19915144, PMID: 28655712).	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 in cell culture (PMID: 29753091) and increased basal kinase activity in an in vitro assay (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, Mar 2024).	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). P124S results in increased Erk1/2 phosphorylation and confers resistance to Mek and Braf inhibitors (PMID: 19915144, PMID: 22197931) and an Egfr antibody (PMID: 33322618) in culture, but has similar induction of cell proliferation and viability levels to wild-type Map2k1 in culture (PMID: 29533785), and therefore, its effect on Map2k1 protein function is unknown.	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 P124L	melanoma	sensitive	PLX4720 + Selumetinib	Preclinical	Actionable	In a preclinical study, combined treatment with Koselugo (selumetinib) and PLX4720 inhibited growth of melanoma cells harboring BRAF V600E and expressing MAP2K1 P124L in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 I99T	melanoma	resistant	CI-1040	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 I99T in melanoma cells harboring BRAF V600E conferred resistance to CI-1040 (PD184352) treatment in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 I103N	melanoma	resistant	CI-1040	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 I103N in melanoma cells harboring BRAF V600E conferred resistance to CI-1040 (PD184352) treatment in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 L115R	melanoma	resistant	CI-1040	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 L115R in melanoma cells harboring BRAF V600E conferred resistance to CI-1040 (PD184352) treatment in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 L115R	melanoma	resistant	PLX4720	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 L115R in melanoma cells harboring BRAF V600E conferred resistance to PLX4720 treatment in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 V211D	melanoma	resistant	CI-1040	Preclinical	Actionable	In a preclinical study, expression of MAP2K1 V211D in melanoma cells harboring BRAF V600E conferred resistance to CI-1040 (PD184352) treatment in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 H119P	melanoma	resistant	Selumetinib	Preclinical	Actionable	In a preclinical study, expression of MAP2K1 H119P in melanoma cells harboring BRAF V600E conferred resistance to Koselugo (selumetinib) treatment in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 L115P	melanoma	resistant	Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 L115P in melanoma cells harboring BRAF V600E conferred resistance to Koselugo (selumetinib) treatment in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 H119P	melanoma	resistant	CI-1040	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 H119P in melanoma cells harboring BRAF V600E conferred resistance to CI-1040 (PD184352) treatment in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 P124L	melanoma	resistant	PLX4720	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 P124L in melanoma cells harboring BRAF V600E conferred resistance to PLX4720 treatment in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 Q56P	melanoma	resistant	Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 Q56P in melanoma cells harboring BRAF V600E conferred resistance to Koselugo (selumetinib) treatment in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 L115P	melanoma	resistant	CI-1040	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 L115P in melanoma cells harboring BRAF V600E conferred resistance to CI-1040 (PD184352) treatment in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 P124L	melanoma	resistant	Selumetinib	Preclinical	Actionable	In a preclinical study, expression of MAP2K1 P124L in melanoma cells harboring BRAF V600E conferred resistance to Koselugo (selumetinib) in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 I111N	melanoma	resistant	CI-1040	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 I111N in melanoma cells harboring BRAF V600E conferred resistance to CI-1040 (PD184352) treatment in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 Q56P	melanoma	resistant	PLX4720	Preclinical	Actionable	In a preclinical study, expression of MAP2K1 Q56P in melanoma cells harboring BRAF V600E conferred resistance to PLX4720 treatment in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 I99T	melanoma	resistant	Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 I99T in melanoma cells harboring BRAF V600E conferred resistance to Koselugo (selumetinib) treatment in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 I103N	melanoma	resistant	Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 I103N in melanoma cells harboring BRAF V600E conferred resistance to Koselugo (selumetinib) treatment in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 I111N	melanoma	resistant	Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 I111N in melanoma cells harboring BRAF V600E conferred resistance to Koselugo (selumetinib) treatment in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 V211D	melanoma	resistant	Selumetinib	Preclinical	Actionable	In a preclinical study, expression of MAP2K1 V211D in melanoma cells harboring BRAF V600E conferred resistance to Koselugo (selumetinib) treatment in culture (PMID: 19915144).	19915144
BRAF V600E MAP2K1 L115R	melanoma	resistant	Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 L115R in melanoma cells harboring BRAF V600E conferred resistance to Koselugo (selumetinib) treatment in culture (PMID: 19915144).	19915144