Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China.
Int J Cancer. 2019 Jan 1;144(1):200-209. doi: 10.1002/ijc.31907. Epub 2018 Oct 31.
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-κB 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 IKKβ 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-κB 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-κB inhibition can improve sensitivity to irradiation and to EGFR-TKIs and can decrease irradiation-induced lung toxicity in lung cancer.
放疗抵抗和表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）耐药以及与治疗相关的肺毒性是肺癌治疗中的严重问题。已有报道称 NF-κB 与放射抵抗有关。因此，我们评估了其对辐射和 EGFR-TKIs 敏感性、辐射诱导的肺毒性以及辐射对 EGFR-TKIs 敏感性的影响。我们使用 IKKβ 抑制剂 IMD 0354 或 p65 耗竭来探讨其在体外和体内对辐射和 EGFR-TKIs 敏感性的影响。我们在辐射诱导的肺纤维化小鼠模型中评估了 IMD 0354 的疗效。辐射增强了 MET 的激活和表达，从而抑制了肺癌细胞对辐射或 EGFR-TKIs 的敏感性。通过 IMD 0354 或 p65 耗竭抑制 NF-κB 可逆转辐射诱导的 MET 激活，增加肺癌细胞对辐射、EGFR-TKIs 及其联合应用的敏感性，无论是在体外还是在体内。此外，IMD 0354 可显著降低辐射诱导肺炎和肺纤维化小鼠模型中的肺毒性。这些发现表明，NF-κB 抑制可提高辐射和 EGFR-TKIs 的敏感性，并降低肺癌中辐射诱导的肺毒性。
