Dysregulation of cellular iron predisposes chemotherapy resistant cancer cells to ferroptosis

Despite centuries of research, metastatic cancer remains incurable due to resistance against all conventional cancer therapeutics. Alternative strategies leveraging non-proliferative vulnerabilities in cancer are required to overcome cancer recurrence. Ferroptosis is an iron dependent cell death pathway that has shown promising pre-clinical activity in several contexts of therapeutic resistant cancer. However, ferroptosis sensitivity is highly variable across tissue types and cell state posing a challenge for clinical translation. We describe a convergent phenotype induced by chemotherapy where cells surviving chemotherapy have similar transcriptomic signatures and dysregulated iron homeostasis, regardless of initial cell type or chemotherapy used. Elevated labile iron levels are counteracted by NRF2 signaling that does not alleviate the amount of labile iron. Selectively inhibiting GPX4 leads to uniform susceptibility to ferroptosis in surviving cells, highlighting the common reliance on lipid peroxidation defenses. Cellular iron dysregulation is a vulnerability of chemoresistant cancer cells that can be leveraged by triggering ferroptosis. STATEMENT OF SIGNIFICANCEWe show that cells surviving chemotherapy are uniformly sensitive to ferroptosis, despite different sensitivity in untreated cells. Ferroptosis sensitivity surprisingly occurs alongside NRF2 signaling, likely due to loss of PCBP1 and accumulated labile iron. Labile iron accumulation as a driver of ferroptosis sensitivity constitutes another starting point for translation of ferroptosis.