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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 Nature structural & molecular biology
Vol 27
Issue 1
Date 2020 Jan
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
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
BRAF L485S missense gain of function - predicted BRAF L485S lies within the protein kinase domain of the Braf protein (UniProt.org). L485S results in increased ELK transcription in a reporter assay (PMID: 16474404), and has been demonstrated to confer Braf inhibitor resistance in cell culture (PMID: 31925410), and therefore, is predicted to lead to a gain of Braf protein function. Y
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 result in 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, May 2020).
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 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
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 compared to cells expressing EML4-ALK 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 MAPK21 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 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 L485S melanoma resistant Dabrafenib Preclinical - Cell culture Actionable In a preclinical study, melanoma cells expressing BRAF L485S demonstrated resistance to Tafinlar (dabrafenib) treatment in culture (PMID: 31925410). 31925410