title: A systematic analysis of the resistance and sensitivity of HER2YVMA receptor tyrosine kinase mutant to tyrosine kinase inhibitors in HER2-positive lung cancer.
abstract: Human epidermal growth factor receptor 2 (HER2) has become a well-established target for the treatment of HER2-positive lung cancer. However, a frequently observed in-frame mutation that inserts amino acid quadruplex Tyr776-Val777-Met778-Ala779 at G776 (G776(YVMA)) in HER2 kinase domain can cause drug resistance and sensitivity, largely limiting the application of reversible tyrosine kinase inhibitors in lung cancer therapy. A systematic investigation of the intermolecular interactions between the HER2(YVMA) mutant and clinical small-molecule inhibitors would help to establish a complete picture of drug response to HER2 G776(YVMA) insertion in lung cancer, and to design new tyrosine kinase inhibitors with high potency and selectivity to target the lung cancer-related HER2(YVMA) mutant. Here, we combined homology modeling, ligand grafting, structure minimization, molecular simulation and binding affinity analysis to profile a number of tyrosine kinase inhibitors against the G776(YVMA) insertion in HER2. It is found that the insertion is far away from HER2 active pocket and thus cannot contact inhibitor ligand directly. However, the insertion is expected to induce marked allosteric effect on some regions around the pocket, including A-loop and hinges connecting between the N- and C-lobes of HER2 kinase domain, which may exert indirect influence to inhibitor binding. Most investigated inhibitors exhibit weak binding strength to both wild-type and mutant HER2, which can be attributed to steric hindrance that impairs ligand compatibility with HER2 active pocket. However, the cognate inhibitor lapatinib and the non-cognate inhibitor bosutinib were predicted to have low affinity for wild-type HER2 but high affinity for HER2(YVMA) mutant, which was confirmed by subsequent kinase assay experiments; the inhibitory potencies of bosutinib against wild-type and mutant HER2 were determined to be IC(50) > 1000 and =27 nM, respectively, suggesting that the bosutinib might be exploited as a selective inhibitor for mutant over wild-type HER2. Structural examination revealed that formation of additional non-bonded interactions such as hydrogen bonds and hydrophobic contacts with HER2 A-loop region due to G776(YVMA) insertion is the primary factor to improve bosutinib affinity upon the mutation.
authors.affiliation: a Institute of Cell Biology, Zhejiang University , Hangzhou , P.R. China .|b Department of Surgical Oncology , Taizhou Hospital, Wenzhou Medical University , Taizhou , P.R. China , and.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Shen
authors.affiliation: c Department of Internal Oncology , Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , P.R. China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Chen
authors.affiliation: b Department of Surgical Oncology , Taizhou Hospital, Wenzhou Medical University , Taizhou , P.R. China , and.
authors.forename: Zhaosheng
authors.initials: Z
authors.lastname: Ma
authors.affiliation: b Department of Surgical Oncology , Taizhou Hospital, Wenzhou Medical University , Taizhou , P.R. China , and.
authors.forename: Bojian
authors.initials: B
authors.lastname: Xie
authors.affiliation: c Department of Internal Oncology , Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , P.R. China.
authors.forename: Xinguang
authors.initials: X
authors.lastname: Cao
authors.affiliation: c Department of Internal Oncology , Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , P.R. China.
authors.forename: Tiejun
authors.initials: T
authors.lastname: Yang
authors.affiliation: c Department of Internal Oncology , Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , P.R. China.
authors.forename: Yuzhou
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: c Department of Internal Oncology , Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , P.R. China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Qin
authors.affiliation: a Institute of Cell Biology, Zhejiang University , Hangzhou , P.R. China .
authors.forename: Jicheng
authors.initials: J
authors.lastname: Li
authors.affiliation: b Department of Surgical Oncology , Taizhou Hospital, Wenzhou Medical University , Taizhou , P.R. China , and.
authors.forename: Feilin
authors.initials: F
authors.lastname: Cao
authors.affiliation: c Department of Internal Oncology , Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , P.R. China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Chen
mesh_terms: D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D016254:Mutagenesis, Insertional; D009154:Mutation / Q000235:genetics*; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000235:genetics*; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D054852:Small Molecule Libraries; C508053:ERBB2 protein, human
keywords: Epidermal growth factor receptor 2; insertion mutation; lung cancer; tyrosine kinase inhibitor