Molecular insight into the T798M gatekeeper mutation-caused acquired resistance to tyrosine kinase inhibitors in ErbB2-positive breast cancer
Molecular insight into the T798M gatekeeper mutation-caused acquired resistance to tyrosine kinase inhibitors in ErbB2-positive breast cancer
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DOI：
10.1016/j.compbiolchem.2018.12.007
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发表时间：
2019-02-01
影响因子：
3.1
通讯作者：
Ma, Baojin
中科院分区：
文献类型：
--
作者：
Lu, Ji;Zhou, Kun;Ma, Baojin
人表皮生长因子受体2（ErbB 2）是转移性乳腺癌的一个有吸引力的治疗靶点。临床上观察到该激酶在其活性位点具有看门突变T798 M，这导致对使用小分子酪氨酸激酶抑制剂的一线靶向乳腺癌治疗的获得性耐药。此前，已经提出了几种理论来解释看门人突变引起的耐药性的分子机制，如阻断抑制剂结合和增加ATP亲和力。在本研究中，三个野生型选择性抑制剂（拉帕替尼，AEE 788和TAK-285）和两个野生型保守抑制剂（Staurosporine和Bosutinib）与野生型ErbB 2及其T798 M突变体的直接结合通过严格的计算分析和结合亲和力测定详细研究。在残基798处用大体积甲硫氨酸取代极性苏氨酸可以分别削弱和改善野生型选择性抑制剂和野生型保留抑制剂的直接结合亲和力。抑制效应是导致野生型选择性抑制剂亲和力降低的原因，而额外的非键合相互作用则有助于野生型保留抑制剂亲和力的增加，从而赋予突变型抑制剂对野生型的选择性。T798 M突变后，星形孢菌素和博舒替尼与ErbB 2激酶结构域的结合亲和力分别提高了11.9倍和2.1倍。结构分析表明，突变Met 798残基的硫醚基团形成了S-pi接触相互作用的非键合网络（对于星形孢菌素）或涉及S的卤键（对于博舒替尼）。
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-pi contact interactions (for Staurosporine) or an S-involving halogen bond (for Bosutinib) forms with the sulfide group of mutant Met798 residue.