FBW7通过调控肺癌干细胞自我更新参与非小细胞肺癌EGFR-TKIs靶向治疗耐药的研究

Despite the high potency of EGFR-TKIs for certain non-small cell lung cancer (NSCLC) patients, acquired resistance severely limits its clinical value, rendering the exploration of resistance mechanisms imperative. Recent studies have shown that lung cancer stem cells serve as the source of resistance to lung cancer targeted therapy, and the ubiquitin-proteasome pathway (UPP) member FBW7 is involved in the regulation of normal and tumor stem cells of several tissue origins, in terms of the maintenance of stemness and differentiation orientation. Our previous study have shown that FBW7 deletion or mutation can trigger NSCLC EGFR-TKIs resistance.This project aims to investigate the role of FBW7 in regulating the self-renewal capacity of lung cancer stem cells by means of CRISPR-cas9 and genetically modified mice and to screen the key molecules mediating this process using protein chips. In addition, we plan to elucidate the mechanisms underlying the regulation of stemness among those key molecules and FBW7 via co-immunoprecipitation and functional experiments. Finally, we aim to validate our findings in clinical lung cancer tissue and blood samples.This study will open up a new research area of regulation of lung cancer stem cells by UPP, and will reveal the new mechanism of EGFR-TKIs acquired resistance which will provide novel potentially targetable molecular to overcome the resistance to EGFR-TKIs.

EGFR-TKIs 是非小细胞肺癌（NSCLC）治疗领域的里程碑，但获得性耐药严重限制其临床价值，探索耐药机制迫在眉睫。最新研究显示肺癌干细胞是肺癌靶向治疗耐药的根源，泛素-蛋白酶体途径(UPP)成员 FBW7参与正常组织干细胞和肿瘤干细胞干性和分化的调控，我们前期研究表明FBW7缺失或突变可引发NSCLC分子靶向药物耐药的发生。本课题将进一步通过CRISPR-cas9基因敲除技术、遗传修饰小鼠等研究 FBW7 对肺癌干细胞自我更新能力的调控作用，通过蛋白质芯片等方法筛选出介导这一作用的关键分子，通过免疫共沉淀和功能学实验阐明该分子与FBW7在肺癌干细胞干性调控中的作用机制，并在临床肺癌组织和血液样本中验证这一发现。本研究将开辟UPP调控肺癌干细胞研究新领域，揭示EGFR-TKIs 获得性耐药新机制，为克服EGFR-TKIs耐药提供新的靶点。

肿瘤干细胞的研究在肺癌的发生发展和治疗扮演了关键的角色，因此通过靶向肿瘤干细胞抑制肿瘤耐药性的探索迫在眉睫。FBW7是E3泛素连接酶，参与泛素-蛋白酶体途径降解蛋白进而调控细胞活动和代谢，我们前期研究发现了FBW7的缺失或者突变可影响靶向药物耐药的发生，我们推测FBW7通过对肺癌干细胞的调节影响肿瘤耐药性的获得，但是具体调节方式并不清楚。本文揭示了FBW7在受到M6A调节后，通过进一步调节MCM6分子影响肺癌干细胞的表达水平，进而对肿瘤的发生，发展和耐药等重要生理机制发挥抑癌效果。阐明了FBW7调节肺癌干性的机制，为肺癌靶向治疗提供了新的思路