Reduced Erlotinib sensitivity of epidermal growth factor receptor-mutant non-small cell lung cancer following cisplatin exposure: a cell culture model of second-line erlotinib treatment.
Reduced Erlotinib sensitivity of epidermal growth factor receptor-mutant non-small cell lung cancer following cisplatin exposure: a cell culture model of second-line erlotinib treatment.
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DOI：
10.1158/1078-0432.ccr-08-0093
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发表时间：
2008-11-01
期刊：
影响因子：
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通讯作者：
Settleman J
中科院分区：
文献类型：
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作者：
Chin TM;Quinlan MP;Singh A;Sequist LV;Lynch TJ;Haber DA;Sharma SV;Settleman J
表皮生长因子受体（EGFR）激酶抑制剂在一部分晚期非小细胞肺癌（NSCLC）患者中诱导显著的临床应答，且此类应答与EGFR激酶结构域内存在体细胞激活突变相关。因此，这些抑制剂之一，厄洛替尼，已被FDA批准作为化疗难治性晚期NSCLC的二线或三线治疗。然而，由于获得性耐药性，应答通常相对短暂，促使研究确定EGFR抑制剂的一线治疗是否可以提供更大的临床益处。NSCLC衍生的细胞系提供了一个强大的系统，用于模拟EGFR突变相关的EGFR抑制剂的敏感性和模拟临床观察到的获得性耐药机制。在厄洛替尼敏感的EGFR突变型NSCLC细胞系的细胞培养模型中，我们检验了既往暴露于铂类药物（NSCLC化疗的标准组成部分）影响随后对厄洛替尼的应答的假设。事实上，最初选择在顺铂中生长的NSCLC细胞表现出对厄洛替尼的敏感性降低5倍，即使在不存在顺铂的情况下增殖顺铂处理的细胞几个月后。顺铂暴露的这种挥之不去的影响似乎反映了PTEN肿瘤抑制活性的变化和通过PI-3激酶/AKT存活途径的持续EGFR非依赖性信号传导。这些临床前研究结果表明，EGFR突变型NSCLC的一线化疗治疗可能会降低EGFR激酶抑制剂后续治疗的获益，并应促使这些抑制剂作为NSCLC一线治疗的进一步临床研究。
Epidermal growth factor receptor (EGFR) kinase inhibitors induce dramatic clinical responses in a subset of non-small cell lung cancer (NSCLC) patients with advanced disease, and such responses are correlated with the presence of somatic activating mutations within the EGFR kinase domain. Consequently, one of these inhibitors, erlotinib, has been FDA-approved as a second- or third-line treatment for chemotherapy-refractory advanced NSCLC. However, responses are typically relatively short-lived due to acquired drug resistance, prompting studies to determine whether first-line treatment with EGFR inhibitors could provide greater clinical benefit. NSCLC-derived cell lines have provided a powerful system for modeling EGFR mutation-correlated sensitivity to EGFR inhibitors and for modeling mechanisms of acquired drug resistance that are observed clinically. In a cell culture model of an erlotinib-sensitive EGFR mutant NSCLC cell line, we tested the hypothesis that prior exposure to platinum agents, a standard component of NSCLC chemotherapy treatment, affects the subsequent response to erlotinib. Indeed, NSCLC cells initially selected for growth in cisplatin exhibit 5-fold reduced sensitivity to erlotinib, even after propagating the cisplatin-treated cells in the absence of cisplatin for several months. This lingering effect of cisplatin exposure appears to reflect changes in PTEN tumor suppressor activity and persistent EGFR-independent signaling through the PI-3 kinase/AKT survival pathway. These pre-clinical findings suggest that first-line chemotherapy treatment of EGFR mutant NSCLCs may reduce the benefit of subsequent treatment with EGFR kinase inhibitors, and should prompt further clinical investigation of these inhibitors as a first-line therapy in NSCLC.