Emergence of epidermal growth factor receptor T790M mutation during chronic exposure to gefitinib in a non-small cell lung cancer cell line
Emergence of epidermal growth factor receptor T790M mutation during chronic exposure to gefitinib in a non-small cell lung cancer cell line
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DOI：
10.1158/0008-5472.can-07-0681
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发表时间：
2007-08-15
期刊：
影响因子：
11.2
通讯作者：
Tanimoto, Mitsune
中科院分区：
文献类型：
--
作者：
Ogino, Atsuko;Kitao, Hiroyuki;Tanimoto, Mitsune
表皮生长因子受体（EGFR）特异性酪氨酸激酶抑制剂吉非替尼可能会在一些携带EGFR激活突变的肺腺癌患者中提供显着的临床反应。然而，长期给予geritinib可能最终诱导此类患者获得性耐药。为了深入了解这一现象的机制，我们将PC-9（一种源自肺腺癌的细胞系，EGFR外显子19缺失15-bp）置于无任何诱变剂的低水平吉非替尼的连续选择压力下，并建立了一种能够在2 μ mol/L吉非替尼存在下生长的亚系（命名为RPC-9）。在该细胞系中，来自突变EGFR的约一半逆转录PCR产物还携带另外的突变（T790 M）。与T790 M在消除geritinib与EGFR结合中的作用一致，吉非替尼处理的RPC-9几乎没有显示出与PC-9细胞不同的EGFR、Akt或Erkl/2的组成性磷酸化的任何降低。有趣的是，转染仅携带15-bp缺失的EGFR逆转了RPC-9细胞对吉非替尼的耐药性。因此，吉非替尼敏感或吉非替尼耐药EGFR之间表达水平的平衡可能决定肺癌对吉非替尼的反应。
The epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitor gefitinib may provide dramatic clinical responses in some patients with pulmonary adenocarcinoma carrying activating mutations of the EGFR. However, prolonged administration of geritinib may eventually induce acquired resistance in such patients. To gain insight into the mechanisms of this phenomenon, we placed PC-9, a cell line derived from pulmonary adenocarcinoma that has a 15-bp deletion in EGFR exon 19, under the continuous selective pressure of low levels of gefitinib without any mutagen, and established a subline that was able to grow in the presence of 2 mu mol/L of gelfitinib (designated RPC-9). In this cell line, about half of the reverse transcription-PCR products from mutated EGFR also carried an additional mutation (T790M). In keeping with the proposed role of T790M in abrogating geritinib binding with EGFR, gefitinib-treated RPC-9 hardly displayed any decrease in the constitutive phosphorylation of EGFR, Akt, or Erkl/2 unlike in PC-9 cells. Interestingly, transfection of the EGFR carrying only a 15-bp deletion reversed the resistance to gefitinib in RPC-9 cells. Thus, the balance of expression levels between gefitinib-sensitive or gefitinib-resistant EGFR may govern the response to gefitinib in lung cancer.