糖酵解酶HK2调控自噬逆转AZD9291耐药的作用和分子机制

三代EGFR-TKI AZD9291是解决一代EGFR-TKI耐药的有效药物，但其同样面临耐药困扰。我们前期工作发现，AZD9291耐药的肺癌细胞自噬水平和糖酵解关键酶HK2明显升高，抑制自噬后耐药性降低。众所周知，糖酵解和自噬是肿瘤获取能量和回收利用代谢中间产物以满足其异常代谢需要的关键机制，二者间的“代谢互补”关系协同促进肿瘤的发展。研究表明，保护性自噬是EGFR-TKI耐药产生的重要机制，HK2可能是肿瘤细胞维持内稳态机制中糖酵解向自噬转化的分子开关。因此，我们推测HK2可能通过调控糖酵解促进自噬从而在AZD9291耐药机制中发挥关键作用。本项目拟研究AZD9291耐药机制中糖酵解及自噬的作用及相互影响机制，探寻糖酵解和自噬间调控的关键节点，以期打破糖酵解和自噬的“代谢互补”关系，寻求克服AZD9291耐药的新策略，具有重要科学意义。

The third-generation EGFR-TKI AZD9291 is an effective drug for curbing the resistance problem of first-generation EGFR-TKI, but it still faces the same problem. Our previous studies found that, AZD9291-resistant lung cancer cells showed significantly higher levels of autophagy and the key enzyme for glycolysis, HK2, and the resistance was decreased when autophagy was suppressed. As we all know, glycolysis and autophagy are two critical mechanisms from which the tumor could obtain energy and recycle metabolic intermediates in order to meet its abnormal metabolic needs. The “ Complementary metabolism” relationship between the two mechanisms has synergistically facilitated the development of tumor. Studies have shown that, protective autophagy is an important mechanism for the development of EGFR-TKI resistance, and HK2 might be the molecular switch that regulates the transition from glycolysis to autophagy. Thus, we speculate that HK2 might play a key role in inducing AZD9291 resistance, mainly by regulating glycolysis and promoting autophagy. This study aimed to investigate the role and mechanisms by which glycolysis and autophagy influence AZD9291 resistance, to identify key factors involved in the regulation of glycolysis and autophagy, to break the “metabolic-complementary” relationship between the two processes, and thus to provide new strategies for overcoming the problem of AZD9291 resistance.