第三代靶向药物奥希替尼对EGFR常见突变及T790M耐药突变的肺癌患者具有显著的疗效，但耐药无法避免，目前耐药机制未被完全阐明。前期研究中我们应用转录组芯片首次发现一个全新的LncRNA-RP11-274H2.3和IL-6在奥希替尼耐药细胞中显著高表达；蟾毒灵可下调RP11-274H2.3和IL-6表达水平，增强奥希替尼抗肿瘤效果。根据LncRNA作用方式、生物信息学预测及前期研究结果，我们推测RP11-274H2.3通过招募NF-κB促进IL-6转录并激活其下游信号通路诱导奥希替尼耐药；蟾毒灵通过下调RP11-274H2.3抑制NF-κB/IL-6信号轴逆转奥希替尼耐药。本项目拟应用质谱分析、RIP、CHIP、结合位点鉴定及双荧光素酶报告基因等技术，从临床、细胞、动物层面深入探讨RP11-274H2.3诱导奥希替尼耐药的机制及蟾毒灵的干预作用，为开发抗癌中药及防治靶向药物耐药提供理论依据

Osimertinib, a third generation EGFR inhibitor, has a significant effect on lung cancer patients with common EGFR mutations and T790M mutations. It is expected to be the first-line treatment for EGFR-mutant non-small cell lung cancer. However, the development of acquired resistance to osimertinib can not be avoided. The precise mechanisms of resistance to osimertinib remain largely unknown. There is not effective strategies to prevent and/or overcome acquired resistance to this agent. LncRNA plays an important role in tumor progression and drug resistance. By using RNA Microarray analysis, we found that LncRNA-RP11-274H2.3 (a new transcript) and IL-6 were highly expressed in the osimertinb-resistant cells, and bufalin could down-regulate RP11-274H2.3 and IL-6 expression levels for the first time. According to the model of LncRNA function, bioinformatics prediction and our previous research results, we speculate that RP11-274H2.3 induces the resistance to osimertinib by recruiting NF-κB, promoting IL-6 transcription and activating its downstream signaling pathway. Bufalin may reverse the resistance to osimertinib by down-regulating RP11-274H2.3 and inhibiting NF-κB/IL-6 axis. Based on these results, we will reveal the mechanisms of RP11-274H2.3-induced resistance to osimertinib and bufalin reverses osimertinib resistance by using Mass Spectrometry、RIP、 CHIP、Deletion Mapping and Luciferase reporter assay. Our study will provide a novel strategy for development of new antitumor drugs and reversion of osimertinib resistance.