Abstract

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.