Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647
Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647
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DOI：
10.1158/1078-0432.ccr-06-2590
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发表时间：
2007-06-15
影响因子：
11.5
通讯作者：
Joly, Alison H.
中科院分区：
文献类型：
--
作者：
Gendreau, Steven B.;Ventura, Richard;Joly, Alison H.
目的：抑制表皮生长因子受体 (EGFR) 的药物已在表达扩增或突变激活 EGFR 的非小细胞肺癌患者亚群中显示出临床益处。然而，由于 EGFR 基因突变的选择，对 ATP 竞争性 EGFR 抑制剂（如厄洛替尼和吉非替尼）产生耐药性，有反应的患者可能会复发。我们在此描述了 EXEL-7647 (XL647) 的活性，这是一种新型谱选择性激酶抑制剂，对 EGF 和血管内皮生长因子受体酪氨酸激酶家族具有有效活性，在体外和体内对野生型 (WT) 和突变型 EGFR 均具有有效活性。 实验设计：使用 A431 和 A431 在细胞测定和体内检查了 EGFR 抑制剂针对 WT 和突变型 EGFR 的活性及其对下游信号转导的影响。 MDA-MB-231（WT EGFR）和 H1975（L858R 和 T790M 突变 EGFR）异种移植肿瘤。结果：EXEL-7647 在体内显示出对 WT EGFR 的有效且长效的抑制作用。此外，EXEL-7647 还可抑制 EGFR 基因中存在双突变（L858R 和 T790M）的厄洛替尼耐药 H1975 细胞系的细胞增殖和 EGFR 通路激活。体内功效研究表明，EXEL-7647 显着抑制 H1975 异种移植肿瘤的生长，并降低肿瘤 EGFR 信号传导和肿瘤血管密度。此外，与厄洛替尼相比，EXEL-7647 显着抑制 MDA-MB-231 异种移植物的生长和血管化，该模型更依赖于血管内皮生长因子受体的信号传导。结论：这些研究为 XL647 在实体瘤和对现有 EGFR 靶向疗法耐药的肿瘤患者中进行临床试验提供了临床前基础。
Purpose: Agents inhibiting the epidermal growth factor receptor (EGFR) have shown clinical benefit in a subset of non-small cell lung cancer patients expressing amplified or mutationally activated EGFR. However, responsive patients can relapse as a result of selection for EGFR gene mutations that confer resistance to ATP competitive EGFR inhibitors, such as erlotinib and gefitinib. We describe here the activity of EXEL-7647 (XL647), a novel spectrum-selective kinase inhibitor with potent activity against the EGF and vascular endothelial growth factor receptor tyrosine kinase families, against both wild-type (WT) and mutant EGFR in vitro and in vivo.Experimental Design: The activity of EGFR inhibitors against WT and mutant EGFRs and their effect on downstream signal transduction was examined in cellular assays and in vivo using A431 and MDA-MB-231 (WT EGFR) and H1975 (L858R and T790M mutant EGFR) xenograft tumors.Results: EXEL-7647 shows potent and long-lived inhibition of the WT EGFR in vivo. In addition, EXEL-7647 inhibits cellular proliferation and EGFR pathway activation in the erlotinib-resistant H1975 cell line that harbors a double mutation (L858R and T790M) in the EGFR gene. In vivo efficacy studies show that EXEL-7647 substantially inhibited the growth of H1975 xenograft tumors and reduced both tumor EGFR signaling and tumor vessel density. Additionally, EXEL-7647, in contrast to erlotinib, substantially inhibited the growth and vascularization of MDA-MB-231 xenografts, a model which is more reliant on signaling through vascular endothelial growth factor receptors.Conclusions: These studies provide a preclinical basis for clinical trials of XL647 in solid tumors and in patients bearing tumors that are resistant to existing EGFR-targeted therapies.