Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors
Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors
复制标题
支链氨基酸代谢重编程协调对 EGFR 酪氨酸激酶抑制剂的耐药性
DOI：
10.1016/j.celrep.2019.06.026
复制
发表时间：
2019-07-09
期刊：
影响因子：
8.8
通讯作者：
Ji, Hongbin
中科院分区：
文献类型：
--
作者：
Wang, Yuetong;Zhang, Jian;Ji, Hongbin
耐药性是有效癌症治疗的重大障碍。尽管表皮生长因子受体（EGFR）突变癌细胞对致死性EGFR酪氨酸激酶抑制剂（TKI）治疗的耐药机制已得到深入研究，但癌细胞在亚致死药物挑战下如何协调适应性反应仍然很大程度上未知。在这里，我们发现 2 小时亚致死 TKI 治疗会在 EGFR 突变肺癌细胞中引发短暂的耐药状态。持续的亚致死治疗增强了这种耐受性，并最终建立了长期的 TKI 耐药性。这种适应性过程涉及 H3K9 去甲基化介导的支链氨基酸氨基转移酶 1 (BCAT1) 上调以及随后的代谢重编程，从而通过减少活性氧 (ROS) 积累来促进 TKI 耐药。 TKI 和 ROS 诱导试剂的联合治疗克服了临床前小鼠模型中的这种耐药性。临床信息分析支持 BCAT1 表达与 EGFR TKI 反应的相关性。我们的研究结果揭示了 BCAT1 参与的代谢重编程在肺癌 TKI 耐药中的重要性。
Drug resistance is a significant hindrance to effective cancer treatment. Although resistance mechanisms of epidermal growth factor receptor (EGFR) mutant cancer cells to lethal EGFR tyrosine kinase inhibitors (TKI) treatment have been investigated intensively, how cancer cells orchestrate adaptive response under sublethal drug challenge remains largely unknown. Here, we find that 2-h sublethal TKI treatment elicits a transient drug-tolerant state in EGFR mutant lung cancer cells. Continuous sublethal treatment reinforces this tolerance and eventually establishes long-term TKI resistance. This adaptive process involves H3K9 demethylation-mediated upregulation of branched-chain amino acid aminotransferase 1 (BCAT1) and subsequent metabolic reprogramming, which promotes TKI resistance through attenuating reactive oxygen species (ROS) accumulation. Combination treatment with TKI- and ROS-inducing reagents overcomes this drug resistance in preclinical mouse models. Clinical information analyses support the correlation of BCAT1 expression with the EGFR TKI response. Our findings reveal the importance of BCAT1-engaged metabolism reprogramming in TKI resistance in lung cancer.