Reduction of PTEN protein and loss of epidermal growth factor receptor gene mutation in lung cancer with natural resistance to gefitinib (IRESSA).
Reduction of PTEN protein and loss of epidermal growth factor receptor gene mutation in lung cancer with natural resistance to gefitinib (IRESSA).
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DOI：
10.1038/sj.bjc.6602559
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发表时间：
2005-05-09
影响因子：
8.8
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中科院分区：
文献类型：
--
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吉非替尼（易瑞沙）是一种表皮生长因子受体（EGFR）酪氨酸激酶（TK）抑制剂，在晚期非小细胞肺癌（NSCLC）中具有抗肿瘤活性。然而，在未经化疗的晚期NSCLC患者中，在标准化疗方案中加入吉非替尼未能提高生存率。这些结果表明，需要改善患者的选择和靶向治疗的组合原理。我们已经确定了亚群的腺癌细胞系，是自然耐吉非替尼，并分析了cDNA表达谱，基因组状态的EGFR基因和信号通路的影响，吉非替尼在这些细胞系，以确定自然获得耐药的关键机制吉非替尼。与亲本细胞系相比，吉非替尼耐药亚群表现出Akt磷酸化增加（不受吉非替尼抑制）、PTEN蛋白表达减少和EGFR基因突变丢失。Akt和PTEN蛋白表达的这些差异在cDNA阵列图谱中并不明显。这些数据表明，（1）EGFR基因突变可能在一些癌细胞中丢失，并具有其他激活Akt的机制，（2）重新引入PTEN或药理学下调组成型PI 3 K-Akt途径活性可能是吉非替尼耐药癌症的有吸引力的治疗策略。
Gefitinib (IRESSA), an epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor, has antitumour activity in the advanced non-small-cell lung cancer (NSCLC) setting. However, in chemotherapy-naïve patients with advanced NSCLC, the addition of gefitinib to standard chemotherapy regimens failed to increase survival. These results suggest the need for improved patient selection and combination rationales for targeted therapies. We have identified subpopulations of an adenocarcinoma cell line that are naturally resistant to gefitinib, and have analysed the cDNA expression profiles, genomic status of EGFR gene and the effect of gefitinib on signalling pathways in these cell lines in order to identify key mechanisms for naturally acquired resistance to gefitinib. Gefitinib-resistant subpopulations demonstrated increased Akt phosphorylation (not inhibited by gefitinib), reduced PTEN protein expression and loss of the EGFR gene mutation when compared with parental cell lines. These differences in Akt and PTEN protein expression were not evident from the cDNA array profiles. These data suggests that (1) the EGFR gene mutation may be possibly lost in some cancer cells with other additional mechanisms for activating Akt, (2) reintroduction of PTEN or pharmacological downregulation of the constitutive PI3K–Akt-pathway activity may be an attractive therapeutic strategy in cancers with gefitinib resistance.
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