Targeting AKR1B1 inhibits glutathione de novo synthesis to overcome acquired resistance to EGFR-targeted therapy in lung cancer
Targeting AKR1B1 inhibits glutathione de novo synthesis to overcome acquired resistance to EGFR-targeted therapy in lung cancer
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靶向 AKR1B1 抑制谷胱甘肽从头合成，克服肺癌对 EGFR 靶向治疗的获得性耐药
DOI：
10.1126/scitranslmed.abg6428
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发表时间：
2021-10-06
影响因子：
17.1
通讯作者：
Zhu, Liang
中科院分区：
文献类型：
--
作者：
Zhang, Ke-Ren;Zhang, Yu-Fei;Zhu, Liang
获得性耐药是肺癌中诸如表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）治疗等分子靶向疗法的一个瓶颈。对耐药机制的更深入理解能够为这一现象提供见解，并有助于开发额外的治疗策略来克服或延缓耐药。在此，我们确定了一种可作为药物靶点的代谢机制，它驱动肺癌细胞系以及患者来源的异种移植小鼠对EGFR - TKIs产生耐药。我们证明醛酮还原酶家族1成员B1（AKR1B1）与信号转导和转录激活因子3（STAT3）相互作用并激活它，从而上调胱氨酸转运体溶质载体家族7成员11（SLC7A11）。这导致肺癌细胞系和异种移植小鼠模型中胱氨酸摄取增加以及向谷胱甘肽从头合成的通量增加、活性氧（ROS）清除、细胞死亡保护以及对EGFR TKI的耐药。使用选择性抑制剂（包括临床批准的抗糖尿病药物依帕司他）抑制AKR1B1，可恢复耐药细胞系对EGFR TKIs的敏感性，并延缓肺癌患者来源的异种移植小鼠的耐药。我们的研究结果表明了一种针对分子靶向疗法耐药的代谢机制，并为克服对EGFR TKIs（包括第三代抑制剂奥希替尼）的耐药提供了一个潜在的治疗靶点。
Description AKR1B1 boosts glutathione de novo synthesis as a metabolic mechanism driving resistance to EGFR-targeted therapy in mouse models of lung cancer. An antidiabetic drug overcomes TKI resistance Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) is common among patients with lung cancer, posing a great need for new therapies to overcome this resistance. Here, Zhang et. al explored metabolic reprogramming in lung cancer and identified that the up-regulation of AKR1B1 led to enhanced glutathione synthesis and resistance to EGFR inhibitors in cell lines and xenograft mouse models. In addition, the antidiabetic drug epalrestat inhibited AKR1B1 and restored sensitivity to EGFR TKIs in patient-derived xenograft tumors. These findings suggest a promising therapeutic strategy to overcome resistance to first- and third-generation EGFR inhibitors in patients with lung cancer. Acquired resistance represents a bottleneck to molecularly targeted therapies such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in lung cancer. A deeper understanding of resistance mechanisms can provide insights into this phenomenon and help to develop additional therapeutic strategies to overcome or delay resistance. Here, we identified a pharmacologically targetable metabolic mechanism that drives resistance to EGFR TKIs in lung cancer cell lines and patient-derived xenograft mice. We demonstrated that aldo-keto reductase family 1 member B1 (AKR1B1) interacts with and activates signal transducer and activator of transcription 3 (STAT3) to up-regulate the cystine transporter solute carrier family 7 member 11 (SLC7A11). This leads to enhanced cystine uptake and flux to glutathione de novo synthesis, reactive oxygen species (ROS) scavenging, protection from cell death, and EGFR TKI drug resistance in lung cancer cell lines and xenograft mouse models. Suppression of AKR1B1 with selective inhibitors, including the clinically approved antidiabetic drug epalrestat, restored the sensitivity of resistant cell lines to EGFR TKIs and delayed resistance in lung cancer patient-derived xenograft mice. Our findings suggest a metabolic mechanism for resistance to a molecularly targeted therapy and provide a potential therapeutic target for overcoming resistance to EGFR TKIs, including the third-generation inhibitor osimertinib.