Non-small cell lung cancers with kinase domain mutations in the epidermal growth factor receptor are sensitive to ionizing radiation
Non-small cell lung cancers with kinase domain mutations in the epidermal growth factor receptor are sensitive to ionizing radiation
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DOI：
10.1158/0008-5472.can-06-2627
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发表时间：
2006-10-01
期刊：
影响因子：
11.2
通讯作者：
Nirodi, Chaitanya S.
中科院分区：
文献类型：
--
作者：
Das, Amit K.;Sato, Mitsuo;Nirodi, Chaitanya S.
表皮生长因子受体（EGFR）酪氨酸激酶结构域（TKD）突变的非小细胞肺癌（nsclc）通常对EGFR酪氨酸激酶抑制剂吉非替尼和厄洛替尼表现出显著的敏感性。电离辐射（IR）经常用于治疗非小细胞肺癌，但很少有人知道肺肿瘤获得性EGFR突变如何影响对IR的反应。由于这具有重要的临床意义，我们研究并发现，与野生型（WT） EGFR nsclc相比，突变型EGFR nsclc对IR的克隆原存活降低了500- 1000倍。在长生不老的人支气管上皮细胞、p53 WT NSCLC （A549）或p53-null NSCLC （NCI-H1299）中外源表达L858R点突变体或Delta E746-E750缺失突变体形式的EGFR，导致对IR的敏感性显著增加。我们发现，大多数突变型EGFR nsclc，包括那些含有继发性吉非替尼抗性T790M突变的nsclc，表现出与放射敏感表型一致的特征，包括DNA修复动力学延迟，er诱导的DNA合成或有丝分裂缺陷，以及细胞凋亡或微核的明显增加。因此，了解EGFR TKD结构域的激活突变如何促进放射敏感性，应该为用放疗有效治疗NSCLC提供新的见解，并可能避免单药耐药的出现。
Non-small cell lung cancers (NSCLCs) bearing mutations in the tyrosine kinase domain (TKD) of the epidermal growth factor receptor (EGFR) often exhibit dramatic sensitivity to the EGFR tvrosine kinase inhibitors gefitinib and erlotinib. Ionizing radiation (IR) is frequently used in the treatment of NSCLC, but little is known how lung tumor-acquired EGFR mutations affect responses to IR. Because this is of great clinical importance, we investigated and found that clonogenic survival of mutant EGFR NSCLCs in response to IR was reduced 500- to 1,000-fold compared with wild-type (WT) EGFR NSCLCs. Exogenous expression of either the L858R point mutant or the Delta E746-E750 deletion mutant form of EGFR in immortalized human bronchial epithelial cells, p53 WT NSCLC (A549), or p53-null NSCLC (NCI-H1299) resulted in dramatically increased sensitivity to IR. We show that the majority of mutant EGFR NSCLCs, including those that contain the secondary gefitinib resistance T790M mutation, exhibit characteristics consistent with a radiosensitive phenotype, which include delayed DNA repair kinetics, defective ER-induced arrest in DNA synthesis or mitosis, and pronounced increases in apoptosis or micronuclei. Thus, understanding how activating mutations in the TKD domain of EGFR contribute to radiosensitivity should provide new insight into effective treatment of NSCLC with radiotherapy and perhaps avoid emergence of single agent drug resistance.