Yosaatmadja Yuliana, Silva Shevan, Dickson James M, Patterson Adam V, Smaill Jeff B, Flanagan Jack U, McKeage Mark J, Squire Christopher J
School of Biological Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
J Struct Biol. 2015 Dec;192(3):539-544. doi: 10.1016/j.jsb.2015.10.018. Epub 2015 Nov 2.
The discovery of genetic drivers of lung cancer in patient sub-groups has led to their use as predictive biomarkers and as targets for selective drug therapy. Some of the most important lung cancer drivers are mutations in the EGFR gene, for example, the exon 19 deletions and the L858R variant that confer sensitivity to the front line drugs erlotinib and gefitinib; the acquired T790M variants confer drug resistance and a poor prognosis. A challenge then in targeting EGFR is to produce drugs that inhibit both sensitising variants and resistance variants, leaving wild type protein in healthy cells unaffected. One such agent is AstraZeneca's "breakthrough" AZD9291 molecule that shows a 200-fold selectivity for T790M/L858R over wild type EGFR. Our X-ray crystal structure reveals the binding mode of AZD9291 to the kinase domain of wild type EGFR.
在肺癌患者亚组中发现的肺癌基因驱动因素已使其被用作预测性生物标志物和选择性药物治疗的靶点。一些最重要的肺癌驱动因素是表皮生长因子受体（EGFR）基因的突变，例如，第19外显子缺失和L858R变体，这些突变使患者对一线药物厄洛替尼和吉非替尼敏感；获得性T790M变体则导致耐药性并预后不良。那么，针对EGFR的一个挑战是生产既能抑制敏感变体又能抑制耐药变体的药物，同时使健康细胞中的野生型蛋白不受影响。阿斯利康的“突破性”AZD9291分子就是这样一种药物，它对T790M/L858R的选择性比对野生型EGFR高200倍。我们的X射线晶体结构揭示了AZD9291与野生型EGFR激酶结构域的结合模式。
