Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation
Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation
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阿法替尼可提高具有获得性 EGFR T790M 突变的非小细胞肺癌细胞对放射的敏感性
DOI：
10.18632/oncotarget.3332
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发表时间：
2015-03-20
期刊：
影响因子：
--
通讯作者：
Ma, Shenglin
中科院分区：
文献类型：
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作者：
Zhang, Shirong;Zheng, Xiaoliang;Ma, Shenglin
阿法替尼是第二代表皮生长因子受体(EGFR)酪氨酸激酶抑制剂，已在具有EGFR激活突变的非小细胞肺癌(NSCLC)患者中显示出显著的临床益处。然而，阿法替尼联合其他治疗方式，包括电离辐射(IR)，其潜在的治疗效果还不是很清楚。在这项研究中，我们从NSCLC PC-9细胞中建立了一个具有继发性EGFR突变(T790M)的Gefitinib耐药细胞亚系(PC-9-GR)，该细胞在长期暴露于不断增加剂量的Gefitinib后。阿法替尼的存在显著增加了辐射对携带获得性T790M的PC-9-GR细胞的杀伤作用，但对携带从头T790M的H1975细胞或表达野生型EGFR的H460细胞无明显影响。在PC-9-GR细胞中，阿法替尼显著阻断EGFR和ERK的基础磷酸化，并导致IR诱导的AKT磷酸化延迟。阿法替尼治疗还导致照射后的PC-9-GR细胞凋亡增加，DNA损伤修复受抑，与IR联合应用可增强PC-9-GR异种移植瘤的生长抑制作用。我们的研究结果提示，在携带获得性T790M突变的肺癌细胞中，阿法替尼作为辐射增敏剂具有潜在的治疗作用，为在携带EGFR T790M突变的非小细胞肺癌细胞中联合应用阿法替尼和辐射的临床试验提供了理论依据。
Afatinib is a second-generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and has shown a significant clinical benefit in non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations. However, the potential therapeutic effects of afatinib combining with other modalities, including ionizing radiation (IR), are not well understood. In this study, we developed a gefitinib-resistant cell subline (PC-9-GR) with a secondary EGFR mutation (T790M) from NSCLC PC-9 cells after chronic exposures to increasing doses of gefitinib. The presence of afatinib significantly increases the cell killing effect of radiation in PC-9-GR cells harboring acquired T790M, but not in H1975 cells with de novo T790M or in H460 cells that express wild-type EGFR. In PC-9-GR cells, afatinib remarkable blocks baseline of EGFR and ERK phosphorylations, and causes delay of IR-induced AKT phosphorylation. Afatinib treatment also leads to increased apoptosis and suppressed DNA damage repair in irradiated PC-9-GR cells, and enhanced tumor growth inhibition when combined with IR in PC-9-GR xenografts. Our findings suggest a potential therapeutic impact of afatinib as a radiation sensitizer in lung cancer cells harboring acquired T790M mutation, providing a rationale for a clinical trial with combination of afatinib and radiation in NSCLCs with EGFR T790M mutation.