Inhibition of NF-κB improves sensitivity to irradiation and EGFR-TKIs and decreases irradiation-induced lung toxicity
Inhibition of NF-κB improves sensitivity to irradiation and EGFR-TKIs and decreases irradiation-induced lung toxicity
复制标题
抑制 NF-κB 可提高对辐射和 EGFR-TKI 的敏感性，并降低辐射引起的肺毒性
DOI：
10.1002/ijc.31907
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发表时间：
2019-01-01
影响因子：
6.4
通讯作者：
Wang, Wei
中科院分区：
文献类型：
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作者：
Wang, Rong;Peng, Shunli;Wang, Wei
对放疗和EGFR酪氨酸激酶抑制剂（EGFR-TKI）的抗性以及治疗相关的肺毒性是肺癌治疗中的严重问题。NF-κ B已被报道与辐射抗性有关。因此，我们评价了其对辐射和EGFR-TKI敏感性的影响;辐射诱导的肺毒性;以及辐射对EGFR-TKI敏感性的影响。我们使用IKK β抑制剂IMD 0354或p65耗竭来探索它们在体外和体内对辐射敏感性和EGFR-TKI的影响。我们评估了IMD 0354在辐射诱导的肺纤维化小鼠模型中的功效。辐射增强MET的活化和表达，从而抑制肺癌细胞对辐射或EGFR-TKI的敏感性。通过IMD 0354或p65耗竭抑制NF-κ B逆转了辐射诱导的MET活化，并增加了肺癌细胞对辐射、EGFR-TKI及其组合的体外和体内敏感性。此外，IMD 0354显著降低了辐射诱导的肺炎和肺纤维化的鼠模型中的肺毒性。这些结果表明，NF-κ B抑制可以提高肺癌对辐射和EGFR-TKI的敏感性，并可以减少辐射诱导的肺毒性。
Resistance to radiotherapy and to EGFR tyrosine kinase inhibitors (EGFR-TKIs), as well as therapy-related lung toxicity, are serious problems in the treatment of lung cancer. NF-kappa B has been reported to be associated with radioresistance. Therefore, we evaluated its effects on sensitivity to irradiation and to EGFR-TKIs; irradiation-induced lung toxicity; and the effects of irradiation on sensitivity to EGFR-TKIs. We used IKK beta inhibitor IMD 0354 or p65 depletion to explore their effects on sensitivity to irradiation and to EGFR-TKIs in vitro and in vivo. We evaluated the efficacy of IMD 0354 in a radiation-induced pulmonary-fibrosis mouse model. Irradiation enhanced activation and expression of MET and therefore suppressed the sensitivity of lung cancer cells to irradiation or EGFR-TKIs. Inhibition of NF-kappa B by IMD 0354 or by p65 depletion reversed irradiation-induced MET activation and increased the sensitivity of lung cancer cells to irradiation, to EGFR-TKIs and to the combination thereof in vitro and in vivo. In addition, IMD 0354 significantly reduced lung toxicity in a murine model of irradiation-induced pneumonia and lung fibrosis. These findings indicated that NF-kappa B inhibition can improve sensitivity to irradiation and to EGFR-TKIs and can decrease irradiation-inducedlung toxicity in lung cancer.