State Key Laboratory of Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; CAS Center for Excellence in Molecular Cell Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
Cell Rep. 2019 Jul 9;28(2):512-525.e6. doi: 10.1016/j.celrep.2019.06.026.
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.
耐药性是有效癌症治疗的重大障碍。尽管已经深入研究了表皮生长因子受体 (EGFR) 突变型癌细胞对致命 EGFR 酪氨酸激酶抑制剂 (TKI) 治疗的耐药机制，但癌细胞如何在亚致死药物挑战下协调适应性反应在很大程度上仍然未知。在这里，我们发现在亚致死 TKI 处理 2 小时后，EGFR 突变型肺癌细胞会产生短暂的药物耐受状态。持续的亚致死处理会加强这种耐受性，并最终建立长期的 TKI 耐药性。这个适应性过程涉及 H3K9 去甲基化介导的支链氨基酸转氨酶 1 (BCAT1) 的上调，以及随后的代谢重编程，通过减轻活性氧 (ROS) 积累来促进 TKI 耐药性。联合使用 TKI 和 ROS 诱导剂在临床前小鼠模型中克服了这种耐药性。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 耐药性中的重要性。
