title: Drug response to HER2 gatekeeper T798M mutation in HER2-positive breast cancer.
abstract: The gatekeeper T798M mutation in HER2 kinase domain has been observed to considerably shift drug sensitivity to HER2 in breast cancer therapy. Here, drug response of clinical tyrosine kinase inhibitors (TKIs) to the mutation was profiled using a synthetic biology protocol. It was found that TKIs can be grouped into three classes in terms of their response behavior to T798M mutation: class I inhibitors exhibit drug resistance upon the mutation, such as lapatinib, TAK-285 and AEE788; class II inhibitors are insensitive to the mutation, such as erlotinib and gefitinib; and class III inhibitors can be sensitized by the mutation, such as staurosporine. However, kinetic study indicated that the mutation has only a modest effect on the binding of substrate ATP to HER2. Binding free energy analysis revealed that the drug response is primarily determined by direct interaction between the kinase and inhibitors, but not by indirect kinase interaction with competitive ATP. This is different to the molecular mechanism of "generic" drug resistance conferring from EGFR gatekeeper T790M mutation, which is caused by increased ATP affinity upon the mutation. Structural analysis of kinase-inhibitor complexes unraveled that HER2 T798M mutation induces significant steric hindrance to class I inhibitors, but can establish additional nonbonded interactions for class III inhibitors.
authors.affiliation: Department of General Surgery, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, China.|Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou, 310022, China.|Zhejiang Chinese Medical University, Hangzhou, 310053, China.|Wenzhou Medical University, Wenzhou, 325035, China.
authors.forename: Xuli
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Li
authors.affiliation: The 2nd Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
authors.forename: Hongchao
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Mao
authors.affiliation: Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Wang
authors.affiliation: College of Life Science, Zhejiang Sci-Tech University, Hangzhou, 310018, China. xfding@zstu.edu.cn.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou, 310022, China. shangnaoxie@sina.cn.
authors.forename: Shangnao
authors.initials: S
authors.lastname: Xie
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D005260:Female; D000077156:Gefitinib; D006801:Humans; D006885:Hydroxybutyrates / Q000494:pharmacology; D000077341:Lapatinib; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006885:Hydroxybutyrates; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011687:Purines; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D019311:Staurosporine; C570404:N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo(3,2-d)pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C489254:AEE 788
keywords: Bioinformatics; Breast cancer; Epidermal growth factor receptor 2; Gatekeeper T798M mutation; Tyrosine kinase inhibitor