Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis

Ok Seon Kwon, Eun Ji Kwon, Hyeon Joon Kong, Jeong Yoon Choi, Yun Jeong Kim, Eun Woo Lee, Wankyu Kim, Haeseung Lee, Hyuk Jin Cha

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Erastin, a synthetic lethal compound against cancer expressing an oncogenic RAS, inhibits cystine/glutamate antiporters and causes ferroptosis. However, despite recent evidence for the mechanisms underlying ferroptosis, molecular biomarkers of erastin-dependent ferroptosis have not been identified. Here, we employed isogenic lung cancer cell models to show that a redox imbalance leads to glutathione depletion and ferroptosis. Subsequent transcriptome analysis of pan-cancer cell lines revealed that the activity of transcription factors, including NRF2 and AhR, serve as important markers of erastin resistance. Based on the integrated expression of genes in the nuclear receptor meta-pathway (NRM), we constructed an NRM model and validated its robustness using an independent pharmacogenomics dataset. The NRM model was further evaluated by sensitivity tests on nine cancer cell lines for which erastin sensitivities had not been determined. Our pharmacogenomics approach has the potential to pave the way for the efficient classification of patients for therapeutic intervention using erastin.

Original languageEnglish
Article number101719
JournalRedox Biology
Volume37
DOIs
StatePublished - Oct 2020

Keywords

  • Aryl hydrocarbon receptor
  • Drug response biomarker
  • Drug sensitivity prediction
  • Elastic net
  • Erastin
  • Ferroptosis
  • NRF2
  • Redox imbalance

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