Abstract 4156: Inhibition of NF-kB improves sensitivity to radiation and EGFR inhibitor and decreases radiation-induced lung toxicity in lung cancer

Abstract

Abstract Combination with EGFR-TKIs and radiation seems to be a good strategy against lung cancer, since radiation could enhance EGFR expression. However, the results of clinical trials were controversial. MET activation was involved in resistance to both radiation and EGFR inhibitor, while NF-kB was reported to closely relate to HGF/MET signaling axis. Furthermore, NF-κB has been proved to play a role in bleomycin-induced pulmonary fibrosis, which could be ameliorated by IKKB inhibitor (IMD-0354). Therefore, we evaluated the influence of NF-kB/MET inhibition to the sensitivity of radiation and EGFR-TKIs in lung cancer cells in vitro and in vivo. we also examined the role of NF-κB in radiation-induced lung toxicity. Our data showed that radiation enhanced activation and expression of MET and EGFR, whereas only activation of MET could be reversed by IMD-0354 and p65 depletion, suggesting that radiation-induced MET activation was mediated by NF-kB signaling. Furthermore, NF-kB inhibition increased radiation-induced DNA damage and apoptosis in lung cancer cells. On the other hand, radiation decreased sensitivity to EGFR inhibitor in EGFR mutant lung cancer cells, while inhibition of NF-kB or MET overcame the resistance. Importantly, IMD-0354 increased sensitivity to radiation, EGFR-TKIs, or their combination in mouse xenograft tumors by arresting cell proliferation and inducing cell apoptosis. Interestingly, IMD-0354 significantly reduced the lung toxicity in a mouse model of radiation-induced pneumonia and lung fibrosis. Our preclinical findings indicated that inhibition of NF-kB/MET could improve sensitivity to radiation and EGFR inhibitor and decrease radiation-induced lung toxicity in lung cancer. Citation Format: Wei Wang, Rong Wang, Shunli Peng, Qi Li, Xiaojuan Zhang, Yueyun Ma. Inhibition of NF-kB improves sensitivity to radiation and EGFR inhibitor and decreases radiation-induced lung toxicity in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4156.