明确表皮生长因子酪氨酸激酶抑制剂（EGFR-TKI）应该与哪种治则中药联合具有重要的临床意义。我们团队已经开展了系列研究：1）流行病学研究发现EGFR突变患者以寒证居多，EGFR-TKI耐药时热证患者显著增多，提示EGFR-TKI具有“温阳”作用，很可能应该与“清热”中药联合；2）清热的清开灵与吉非替尼在细胞模型中具有协同作用，温阳的参附具有拮抗作用，支持上述假说；3）预实验发现清开灵+吉非替尼组有氧呼吸增加、无氧酵解减少，与文献中吉非替尼耐药干细胞的糖酵解代谢特征相反，而有氧呼吸及活性氧簇（ROS）是干细胞分化的重要信号，因此清热中药很可能通过代谢重排与吉非替尼发挥协同作用。本研究一方面利用多种清热中成药注射液验证EGFR-TKI是否应该与清热治则联合；另一方面以3D-肺癌类器官为模型模拟干细胞憩室，从干细胞能量代谢及ROS角度探讨其机制，为中医药联合EGFR-TKI提供治则方面的指导

It is very important for Traditional Chinese Medicine (TCM) clinical practice to know which TCM treatment principle should be combined with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Our team has been working on this purpose for several years, and serial of researches have been carried out, including: 1) Clinical epidemiology study found that patients with EGFR gene mutation were more with Yin-cold TCM syndrome type. After EGFR-TKI treatment, resistant patients were more with Yang-heat syndrome type. Thus, gefitinib had kind of TCM “warming-yang” effect. According to TCM theory, it should be combined with “clearing-heat” TCM drugs. 2) Experiments in A549 and H1650 cell lines indicated that Qing-kai-ling (QKL), a kind of “clearing-heat” TCM injection, had synergistic effect with gefitinib, while Shen-fu, a kind of “warming-yang” TCM injection, had antagonism effect. This also agreed with our hypothesis. 3) Our previous experiments found that cells treated with QKL+gefitinib had less glycolysis and more oxidative phosphorylation (OXPHOS). Studies reported that gefetinib resistant cancer stem cells had more glycolysis, which is much different from cells treated with QKL+gefitinib. Interestingly, another study indicated that OXPHOS in stem cells increased ROS, and then induced differentiation. Therefore, the synergistic effect of QKL to gefitinib may result from the metabolism reprogramming. In this study, we will use kinds of TCM injections with “clearing-heat” effect to prove our hypothesis that EGFR-TKI should be combined with “clearing-heat” treatment principle. What’s more, we will use the lung cancer 3D-organoid models, the preferred model for stem cell researches because of the stem cell niches, to find out the metabolism and ROS mechanism of this synergistic effect. Our research will be the theoretical basis for TCM treatment principle combined with EGFR-TKIs.