Inhibition of NF‐κB improves sensitivity to irradiation and EGFR‐TKIs and decreases irradiation‐induced lung toxicity. Issue 1 (31st October 2018)

• Record Type: Journal Article
• Authors: Wang, Rong; Peng, Shunli; Zhang, Xiaojuan; Wu, Zhenming; Duan, Hezhen; Yuan, Yawei; Wang, Wei
• Is Part Of: International journal of cancer. Volume 144:Issue 1(2019)
• Page Start: 200
• Page End: 209
• Publication Date: 2018-10-31
• Subjects: NF‐κB -- irradiation -- EGFR‐TKIs -- resistance -- lung toxicity; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.31907
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : 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. Abstract : What's new? The efficacy of lung cancer treatment is limited by various factors, including resistance to radiotherapy and epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs). The mechanisms underlying therapeutic resistance, however, remain unclear. In this study, investigation of the effects on treatment sensitivity of NF‐κB, a factor previously associated with radioresistance in cancer cells, shows that irradiation reduces lung cancer cell susceptibility to EGFR‐TKIs. This effect was overcome by NF‐κB inhibition, which increased radiosensitivity via effects on MET signaling. The findings indicate that irradiation‐induced NF‐κB activation and subsequent MET upregulation serve a critical role in therapeutic resistance in lung cancer.