Dysregulation of Labile Iron Predisposes Chemotherapy Resistant Cancer Cells to Ferroptosis

Area of Science:

• Oncology
• Cell Death Pathways
• Cancer Therapeutics Resistance

Background:

• Metastatic cancer remains largely incurable due to therapeutic resistance.
• Ferroptosis, an iron-dependent cell death, shows promise against resistant cancers but exhibits variable sensitivity.
• Overcoming recurrence requires strategies targeting non-proliferative vulnerabilities.

Purpose of the Study:

• To identify common vulnerabilities in chemotherapy-surviving cancer cells.
• To investigate the role of iron homeostasis in chemoresistance.
• To explore ferroptosis as a therapeutic strategy for chemoresistant cancers.

Main Methods:

• Analysis of cellular phenotype and iron homeostasis in chemotherapy-surviving cells.
• Investigation of NRF2 signaling and its impact on iron levels.
• Selective inhibition of GPX4 to assess ferroptosis susceptibility.

Main Results:

• Chemotherapy survivors share a phenotype of dysregulated iron homeostasis, irrespective of cell type or drug.
• Elevated labile iron in survivors is partially managed by NRF2 signaling but not resolved.
• GPX4 inhibition uniformly induces ferroptosis in these surviving cells, revealing reliance on lipid peroxidation defenses.

Conclusions:

• Cellular iron dysregulation is a conserved vulnerability in chemoresistant cancer cells.
• Targeting ferroptosis by inhibiting GPX4 offers a potential strategy to overcome chemoresistance.
• Leveraging iron dysregulation through ferroptosis induction may improve cancer treatment outcomes.