Small in-frame deletion in the epidermal growth factor receptor as a target for ZD6474
Small in-frame deletion in the epidermal growth factor receptor as a target for ZD6474
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DOI：
10.1158/0008-5472.can-04-2360
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发表时间：
2004-12-15
期刊：
影响因子：
11.2
通讯作者：
Nishio, K
中科院分区：
文献类型：
--
作者：
Arao, T;Fukumoto, H;Nishio, K
ZD 6474是一种血管内皮生长因子受体-2（VEGFR-2/KDR）酪氨酸激酶抑制剂，对表皮生长因子受体（EGFR）酪氨酸激酶具有额外活性。ZD 6474在体内抑制多种肿瘤模型的血管生成和生长。吉非替尼（“易瑞沙”）是一种选择性EGFR酪氨酸激酶抑制剂，其阻断与癌细胞增殖有关的信号转导途径。在此，直接在8种癌细胞系中体外检测了吉非替尼和ZD 6474抑制肿瘤细胞增殖的能力，并观察到吉非替尼和ZD 6474的IC 50值之间存在强相关性（r = 0.79）。在对ZD 6474的敏感性与EGFR或VEGFR表达水平之间未观察到相关性。观察到NSCLC细胞系PC-9对吉非替尼和ZD 6474超敏，并检测到EGFR中ATP结合位点（外显子19）的小（15 bp）框内缺失（delE 746-A750型缺失）。为了阐明EGFR缺失突变参与细胞对ZD 6474的敏感性，我们检查了该药物对表达缺失EGFR的HEK 293稳定转染子的影响，该缺失EGFR设计为与PC-9细胞（293-pDelta 15）中观察到的缺失位点相同。与表达野生型EGFR的转染子相比，这些细胞对ZD 6474的敏感性高60倍。与野生型EGFR细胞相比，ZD 6474对突变型EGFR磷酸化的抑制作用为10倍。总之，结果表明EGFR中的小框内缺失增加了细胞对ZD 6474的敏感性。
ZD6474 is an inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2/KDR) tyrosine kinase, with additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. ZD6474 inhibits angiogenesis and growth of a wide range of tumor models in vivo. Gefitinib ("Iressa") is a selective EGFR tyrosine kinase inhibitor that blocks signal transduction pathways implicated in cancer cell proliferation. Here, the ability of gefitinib and ZD6474 to inhibit tumor cell proliferation was examined directly in eight cancer cell lines in vitro, and a strong correlation was noted between the IC50 values of gefitinib and ZD6474 (r = 0.79). No correlation was observed between the sensitivity to ZD6474 and the level of EGFR or VEGFR expression. The NSCLC cell line PC-9 was seen to be hypersensitive to gefitinib and ZD6474, and a small (15-bp) in-frame deletion of an ATP-binding site (exon 19) in the EGFR was detected (delE746-A750-type deletion). To clarify the involvement of the deletional mutation of EGFR in the cellular sensitivity to ZD6474, we examined the effect of this agent on HEK293 stable transfectants expressing deletional EGFR that designed as the same deletion site observed in PC-9 cells (293-pDelta15). These cells exhibited a 60-fold higher sensitivity to ZD6474 compared with transfectants expressing wild-type EGFR. ZD6474 inhibited the phosphorylation of the mutant EGFR by 10-fold compared with cells with wild-type EGFR. In conclusion, the findings suggested that a small in-frame deletion in the EGFR increased the cellular sensitivity to ZD6474.