EGFR抑制剂带了来肺癌治疗的革命。由于放射能够提高肺癌细胞EGFR的表达，EGFR抑制剂联合放疗成为理论上最佳治疗模式之一。然而临床实验的疗效并不令人满意，因此提高肺癌对放疗与EGFR抑制剂联合治疗的敏感性有着重要意义。我们已经报道了HGF通过c-MET途径诱导EGFR抑制剂耐药。同时，我们还报道了c-MET的活化与辐射抵抗相关。本项目旨在探讨c-MET在EGFR抑制剂与放疗联合治疗中的作用。初步研究发现：放射提高了c-MET分子的活化与表达进而促进放射抵抗，而抑制NF-kappaB信号则可逆转这一过程。另一方面，抑制c-MET信号可提高放射后的肺癌细胞对EGFR抑制剂的敏感性。本项目拟采用体外培养、基因沉默、小鼠肿瘤模型以及组织标本染色等技术，旨在获得NF-kappaB/c-MET参与放射联合EGFR抑制剂敏感性的可靠证据，为开发新的肺癌治疗模式提供科学依据。

Molecular target therapy with EGFR inhibitor has brought a revolution to lung cancer therapy. Since irradiation has been shown to be able to enhance EGFR expression in lung cancer cells, combined therapy with EGFR inhibitor and radiation seems to be one of the best therapeutic strategy against lung cancer in theory. However, the results of clinical trials with this combination were not as satisfactory as expected. This indicates that unknown mechanism was responsible for resistance to EGFR inhibitor, radiation, or both. Previously, we have reported that HGF induces EGFR inhibitor resistance in lung cancer cells by activating c-MET receptor and the downstream PI3K/Akt pathway. More recently, we reported that c-MET and PI3K/Akt activation were related to cancer radioresistance. In the present study, we are going to explore the role of c-MET in the combined therapy with EGFR inhibitor and radiation in lung cancer. In the preliminary experiments, we have found that radiation enhanced the activation and expression of c-MET receptor, which could be reversed by inhibition of NF-kappa B signaling. Interestingly, inhibition of NF-kappa B could not abrogate radiation-induced EGFR activation and overexpression. This data indicated that radiation-induced aberrant activation of c-MET, but not EGFR, were mediated by NF-kappa B signaling pathway. On the other hand, inhibition of c-MET successfully increased the susceptibility to EGFR inhibitor in radiation pretreated lung cancer cells. In future study, we will employ techniques including in vitro cell experiments, gene silence, xenograft mouse models, and immunohistochemistry with tumor tissues from patients, to obtain strong evidences of NF-kappa B/c-MET relating to sensitivity of the combination of EGFR inhibitor and radiation. This study may provide scientific basis to novel therapeutic strategy against lung cancer with higher efficacy.