A novel oncogene-selective sensitivity to synchronous ferroptotic cell death following nutrient modulation


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Ioannis Poursaitidis1,Xiaomeng Wang1,Thomas Crighton1,Richard Lamb1
1University of Liverpool

Abstract

Background

Background

Cancer cells undergo metabolic adaptations to support high nutrient demand. Our initial hypothesis suggests that cancer cells may exhibit metabolic vulnerabilities with respect to their requirement for specific amino acid nutrients. Support for this idea is found in acute lymphoblastic leukemias (ALL) lacking asparagine synthase that rely on exogenous asparagine and die by apoptosis following administration of asparaginase.

Method

To identify in vitro requirements for specific nutrient amino acids to support viability, we selectively depleted individual amino acids from diploid isogenic Human Mammary Epithelial (HME) cells expressing commonly activated oncogenes. Further analyses included cell viability assays, FACS measurement of ROS, Western blotting for protein quantification and siRNA mediated knockdown of protein expression. 

Results

Cysteine deprivation was found to lead to increased cell death of cells expressing an activated epidermal growth factor receptor (EGFR). EGFR-mutant cells underwent an iron-dependent mode of death known as ferroptosis associated with increased generation of reactive oxygen species (ROS). Elevated ROS species included the formation of lipid peroxides, and was reversed by addition of ROS scavengers that also maintained cell viability.  Pharmacological inhibition of EGFR or mitogen-activated protein kinase (MAPK) signalling was found to block cell death and ROS production and was associated with increased expression of glutathione peroxidase 4 (GPX4), an enzyme that detoxifies lipid peroxides. Genetic knockdown of GPX4 sensitised wild type and EGFR inhibitor-treated EGFR mutant cells to ferroptosis.

Conclusion

Our results indicate that the presence of common oncogenic mutations can render cells sensitive to the depletion of a specific nutrient by inhibiting their antioxidant capacity. These findings therefore suggest a potentially novel anti-cancer therapy based on the inability of some MAPK-driven cancer cells to overcome oxidative stress following nutrient depletion.