Gendreau Steven B, Ventura Richard, Keast Paul, Laird A Douglas, Yakes F Michael, Zhang Wentao, Bentzien Frauke, Cancilla Belinda, Lutman Jeffery, Chu Felix, Jackman Lisa, Shi Yongchang, Yu Peiwen, Wang Jing, Aftab Dana T, Jaeger Christopher T, Meyer Stephanie M, De Costa Anushka, Engell Kelly, Chen Jason, Martini Jean-Francois, Joly Alison H
Exelixis, Inc., South San Francisco, California 94083, USA.
Clin Cancer Res. 2007 Jun 15;13(12):3713-23. doi: 10.1158/1078-0432.CCR-06-2590.
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.
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.
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.
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.
抑制表皮生长因子受体（EGFR）的药物已在一部分表达扩增或突变激活型EGFR的非小细胞肺癌患者中显示出临床疗效。然而，有反应的患者可能会因选择出对ATP竞争性EGFR抑制剂（如厄洛替尼和吉非替尼）产生耐药性的EGFR基因突变而复发。我们在此描述了新型谱选择性激酶抑制剂EXEL-7647（XL647）在体外和体内对野生型（WT）和突变型EGFR的活性，该抑制剂对EGF和血管内皮生长因子受体酪氨酸激酶家族具有强效活性。
在细胞试验和体内实验中，使用A431和MDA-MB-231（WT EGFR）以及H1975（L858R和T790M突变型EGFR）异种移植瘤来检测EGFR抑制剂对WT和突变型EGFR的活性及其对下游信号转导的影响。
EXEL-7647在体内对WT EGFR显示出强效且持久的抑制作用。此外，EXEL-7647抑制了厄洛替尼耐药的H1975细胞系中的细胞增殖和EGFR途径激活，该细胞系在EGFR基因中存在双突变（L858R和T790M）。体内疗效研究表明，EXEL-7647显著抑制了H1975异种移植瘤的生长，并降低了肿瘤EGFR信号传导和肿瘤血管密度。此外，与厄洛替尼不同，EXEL-7647显著抑制了MDA-MB-231异种移植瘤（一种更依赖血管内皮生长因子受体信号传导的模型）的生长和血管生成。
这些研究为XL647在实体瘤以及对现有EGFR靶向治疗耐药的肿瘤患者中的临床试验提供了临床前依据。
