MYCN -Amplified Neuroblastoma Is Addicted to Iron and Vulnerable to Inhibition of the System Xc-/Glutathione Axis

• Published in: Cancer research (Chicago, Ill.) Ill.), 2021-04, Vol.81 (7), p.1896-1908
• Main Authors: Floros, Konstantinos V, Cai, JinYang, Jacob, Sheeba, Kurupi, Richard, Fairchild, Carter K, Shende, Mayuri, Coon, Colin M, Powell, Krista M, Belvin, Benjamin R, Hu, Bin, Puchalapalli, Madhavi, Ramamoorthy, Sivapriya, Swift, Kimberly, Lewis, Janina P, Dozmorov, Mikhail G, Glod, John, Koblinski, Jennifer E, Boikos, Sosipatros A, Faber, Anthony C
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - pharmacology; Antioxidants - therapeutic use; Auranofin - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Child; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Ferroptosis - drug effects; Ferroptosis - genetics; Gene Amplification; Gene Expression Regulation, Enzymologic - physiology; Glutathione - metabolism; Humans; Iron - metabolism; Iron - pharmacology; Male; Mice; Mice, Inbred NOD; Mice, Transgenic; N-Myc Proto-Oncogene Protein - genetics; Neuroblastoma - drug therapy; Neuroblastoma - genetics; Neuroblastoma - metabolism; Neuroblastoma - pathology; Oxazoles - pharmacology; Oxazoles - therapeutic use; Phospholipid Hydroperoxide Glutathione Peroxidase - antagonists & inhibitors; Phospholipid Hydroperoxide Glutathione Peroxidase - genetics; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Piperazines - pharmacology; Piperazines - therapeutic use; Sulfasalazine - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-20-1641

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