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.

中文翻译：

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靶向AKR1B1抑制谷胱甘肽从头合成以克服肺癌对EGFR靶向治疗的获得性耐药

获得性耐药是分子靶向治疗的瓶颈，例如肺癌的表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂 (TKI) 治疗。对耐药机制的更深入了解可以提供对这种现象的见解，并有助于开发额外的治疗策略来克服或延迟耐药性。在这里，我们确定了一种药理学靶向代谢机制，该机制驱动肺癌细胞系和患者来源的异种移植小鼠对 EGFR TKI 的耐药性。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，从而上调胱氨酸转运蛋白溶质载体家族 7 成员 11 (SLC7A11)。这导致增强的胱氨酸摄取和谷胱甘肽从头合成的通量，肺癌细胞系和异种移植小鼠模型中的活性氧 (ROS) 清除、细胞死亡保护和 EGFR TKI 耐药性。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，恢复了耐药细胞系对 EGFR TKI 的敏感性，并延迟了肺癌患者来源的异种移植小鼠的耐药性。我们的研究结果表明了对分子靶向治疗耐药的代谢机制，并为克服对 EGFR TKI（包括第三代抑制剂奥希替尼）的耐药性提供了潜在的治疗靶点。包括临床批准的抗糖尿病药物依帕司他，恢复了耐药细胞系对 EGFR TKI 的敏感性，并延迟了肺癌患者来源的异种移植小鼠的耐药性。我们的研究结果表明了对分子靶向治疗耐药的代谢机制，并为克服对 EGFR TKI（包括第三代抑制剂奥希替尼）的耐药性提供了潜在的治疗靶点。包括临床批准的抗糖尿病药物依帕司他，恢复了耐药细胞系对 EGFR TKI 的敏感性，并延迟了肺癌患者来源的异种移植小鼠的耐药性。我们的研究结果表明了对分子靶向治疗耐药的代谢机制，并为克服对 EGFR TKI（包括第三代抑制剂奥希替尼）的耐药性提供了潜在的治疗靶点。