Molecular insight into the T798M gatekeeper mutation-caused acquired resistance to tyrosine kinase inhibitors in ErbB2-positive breast cancer. (February 2019)

• Record Type: Journal Article
• Authors: Lu, Ji; Zhou, Kun; Yin, Xiaoxing; Xu, Han; Ma, Baojin
• Is Part Of: Computational biology and chemistry. Volume 78(2019)
• Page Start: 290
• Page End: 296
• Publication Date: 2019-02
• Subjects: Epidermal growth factor receptor 2 -- Gatekeeper mutation -- Tyrosine kinase inhibitor -- Acquired resistance -- Breast cancer; Chemistry -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; Biochemistry -- Data processing; Biology -- Data processing; Molecular biology -- Data processing; Periodicals; Electronic journals; 542.85
• DOI: 10.1016/j.compbiolchem.2018.12.007
• Languages: English
• ISSNs: 1476-9271

Abstract

Graphical abstract: Highlights: Molecular mechanism of T798M-caused drug resistance in ErbB2-positive breast cancer therapy is investigated. Mutation-introduced hindrance effect is responsible for the acquired resistance to wide type-selective inhibitors. Mutation can form additional nonbonded interactions with wide type-sparing inhibitors. A S-involving halogen bond between Bosutinib and the sulfide group of Met798 residue is observed. Abstract: Human epidermal growth factor receptor 2 (ErbB2) is an attractive therapeutic target for metastatic breast cancer. The kinase has been clinically observed to harbor a gatekeeper mutation T798M in its active site, which causes acquired resistance to the first-line targeted breast cancer therapy with small-molecule tyrosine kinase inhibitors. Previously, several theories have been proposed to explain the molecular mechanism of gatekeeper mutation-caused drug resistance, such as blocking of inhibitor binding and increasing of ATP affinity. In the current study, the direct binding of three wild type-selective inhibitors (Lapatinib, AEE788 and TAK-285) and two wild type-sparing inhibitors (Staurosporine and Bosutinib) to the wild-type ErbB2 and its T798M mutant are investigated in detail by using rigorous computational analysis and binding affinity assay. Substitution of the polar threonine with a bulky methionine at residue 798 can impair and improve the direct binding affinity of wild type-selective and wild type-sparing inhibitors, respectively. Hindrance effect is responsible for the affinity decrease of wild type-selective inhibitors, while additional nonbonded interactions contribute to the affinity increase of wild type-sparing inhibitors, thus conferring selectivity to the inhibitors for mutant over wild type. The binding affinity of Staurosporine and Bosutinib to ErbB2 kinase domain is improved by 11.9-fold and 2.1-fold upon T798M mutation, respectively. Structural analysis reveals that a nonbonded network of S–π contact interactions (for Staurosporine) or an S-involving halogen bond (for Bosutinib) forms with the sulfide group of mutant Met798 residue.