Reference Detail

Ref Type

Journal Article

PMID

(31925410)

Authors

Persky NS, Hernandez D, Do Carmo M, Brenan L, Cohen O, Kitajima S, Nayar U, Walker A, Pantel S, Lee Y, Cordova J, Sathappa M, Zhu C, Hayes TK, Ram P, Pancholi P, Mikkelsen TS, Barbie DA, Yang X, Haq R, Piccioni F, Root DE, Johannessen CM

Title

Defining the landscape of ATP-competitive inhibitor resistance residues in protein kinases.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature structural & molecular biology	27	1	2020 Jan	92-104	Nat Struct Mol Biol

URL

Abstract Text

Kinases are involved in disease development and modulation of their activity can be therapeutically beneficial. Drug-resistant mutant kinases are valuable tools in drug discovery efforts, but the prediction of mutants across the kinome is challenging. Here, we generate deep mutational scanning data to identify mutant mammalian kinases that drive resistance to clinically relevant inhibitors. We aggregate these data with subsaturation mutagenesis data and use it to develop, test and validate a framework to prospectively identify residues that mediate kinase activity and drug resistance across the kinome. We validate predicted resistance mutations in CDK4, CDK6, ERK2, EGFR and HER2. Capitalizing on a highly predictable residue, we generate resistance mutations in TBK1, CSNK2A1 and BRAF. Unexpectedly, we uncover a potentially generalizable activation site that mediates drug resistance and confirm its impact in BRAF, EGFR, HER2 and MEK1. We anticipate that the identification of these residues will enable the broad interrogation of the kinome and its inhibitors.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
MAP2K1	I99G	missense	gain of function - predicted	MAP2K1 I99G lies within the protein kinase domain of the Map2k1 protein (UniProt.org). I99G results in increased Erk2 phosphorylation and confers resistance to some Mek and Braf inhibitors in culture (PMID: 31925410), and therefore, is predicted to lead to a gain of Map2k1 protein function.	Y
MAP2K1	I99M	missense	unknown	MAP2K1 I99M lies within the protein kinase domain of the Map2k1 protein (UniProt.org). I99M has been identified in the scientific literature (PMID: 31925410), but has not been biochemically characterized and therefore, its effect on Map2k1 protein function is unknown (PubMed, Mar 2025).
MAP2K1	I99T	missense	gain of function - predicted	MAP2K1 I99T lies within the protein kinase domain of the Map2k1 protein (UniProt.org). I99T results in increased Erk2 phosphorylation and confers resistance to some Mek and Braf inhibitors in culture (PMID: 31925410), and therefore, is predicted to lead to a gain of Map2k1 protein function.	Y
BRAF	I463W	missense	unknown	BRAF I463W lies within the protein kinase domain of the Braf protein (UniProt.org). I463W has been demonstrated to confer resistance to some Braf inhibitors in culture (PMID: 31925410), but has not been biochemically characterized and therefore, its effect on Braf protein function is unknown (PubMed, Mar 2025).	Y
BRAF	L485S	missense	gain of function - predicted	BRAF L485S lies within the protein kinase domain of the Braf protein (UniProt.org). L485S is predicted to confer a gain of function to Braf as indicated by increased kinase activity in an in vitro assay (PMID: 18413255), and has been demonstrated to confer Braf inhibitor resistance in cell culture (PMID: 31925410).	Y

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF I463W BRAF V600E	melanoma	resistant	Dabrafenib	Preclinical - Cell culture	Actionable	In a preclinical study, melanoma cells harboring BRAF V600E and expressing BRAF I463W or expressing BRAF V600E and I463W in cis demonstrated resistance to Tafinlar (dabrafenib) treatment in culture (PMID: 31925410).	31925410
BRAF L485S BRAF V600E	melanoma	resistant	Dabrafenib	Preclinical - Cell culture	Actionable	In a preclinical study, expression of BRAF L485S in melanoma cells harboring BRAF V600E conferred resistance to Tafinlar (dabrafenib) treatment in culture (PMID: 31925410).	31925410
BRAF V600E MAP2K1 I99G	melanoma	resistant	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 I99G demonstrated resistance to Mekinist (trametinib) treatment in culture (PMID: 31925410).	31925410
BRAF V600E MAP2K1 I99G	melanoma	resistant	Dabrafenib	Preclinical - Cell culture	Actionable	In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 I99G demonstrated resistance to Tafinlar (dabrafenib) treatment in culture (PMID: 31925410).	31925410
BRAF V600E MAP2K1 I99M	melanoma	sensitive	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 I99M demonstrated sensitivity to Mekinist (trametinib) treatment similar to cells expressing wild-type MAP2K1 in culture (PMID: 31925410).	31925410
BRAF V600E MAP2K1 I99M	melanoma	sensitive	Dabrafenib	Preclinical - Cell culture	Actionable	In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 I99M demonstrated sensitivity to Tafinlar (dabrafenib) treatment similar to cells expressing wild-type MAP2K1 in culture (PMID: 31925410).	31925410
BRAF V600E MAP2K1 I99T	melanoma	resistant	Dabrafenib	Preclinical - Cell culture	Actionable	In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 I99T demonstrated resistance to Tafinlar (dabrafenib) treatment in culture (PMID: 31925410).	31925410
BRAF V600E MAP2K1 I99T	melanoma	resistant	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 I99T demonstrated resistance to Mekinist (trametinib) treatment in culture (PMID: 31925410).	31925410
BRAF V600E MAP2K1 S218D MAP2K1 S222D	melanoma	resistant	Dabrafenib	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 S218D and S222D in melanoma cells harboring BRAF V600E conferred resistance to Tafinlar (dabrafenib) treatment in culture (PMID: 31925410).	31925410
EML4 - ALK ALK L1152R	lung cancer	resistant	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, lung cancer cells expressing ALK L1152R in the context of EML4-ALK demonstrated resistance to Zykadia (ceritinib) treatment in culture (PMID: 31925410).	31925410

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