Mismanagement of Cellular Iron Leads to Ferroptosis Susceptibility in Cancer Cells Surviving Chemotherapy

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 PC3 (prostate cancer cell line) were treated with cisplatin and surviving cells were analyzed 1, 5 and 10 days following chemotherapy (DPT). PC3 cells were treated with docetaxel and surviving cells were analyzed 1, 5, 10 days following chemotherapy. SIngle cell RNA sequencing was performed on untreated cell lines and surviving cells 1, 5, and 10 DPT in biological triplicate. Parse Biosciences sequencing is done by combinatorial barcoding, whereby cells from every sample type is present in each sublibrary. Sublibraries are sequenced and individual cells called by barcode identifier.