MYCN-amplified neuroblastoma is addicted to iron and vulnerable to inhibition of the system Xc-/glutathione axis

摘要: MYCN is amplified in 20% to 25% of neuroblastoma, and MYCN-amplified neuroblastoma contributes a large percent pediatric cancer–related deaths. Therapy improvements for this subtype cancer are high priority. Here we uncover MYCN-dependent therapeutic vulnerability neuroblastoma. Namely, rewires the cell through expression key receptors, ultimately enhancing iron influx increased import transferrin receptor 1. Accumulating causes reactive oxygen species (ROS) production, neuroblastomas show enhanced reliance on system Xc- cystine/glutamate antiporter ROS detoxification transcription receptor. This dependence creates marked targeting Xc-/glutathione (GSH) pathway with ferroptosis inducers. can be exploited therapy FDA-approved rheumatoid arthritis drugs sulfasalazine (SAS) auranofin: MYCN-amplified, patient-derived xenograft models, both therapies blocked growth induced ferroptosis. SAS auranofin activity was largely mitigated by inhibitor ferrostatin-1, antioxidants like N-acetyl-L-cysteine, or scavenger deferoxamine (DFO). DFO reduced auranofin-induced ROS, further linking capture ROS-inducing drugs. These data an oncogene caused accumulation subsequent Xc-/GSH pathway. Significance: study shows how increases intracellular levels GSH demonstrates antitumor models