Loftus Luke V, Rolle Louis T A, Wang Bowen, Pienta Kenneth J, Amend Sarah R
Cellular and Molecular Medicine Program, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
Cancer Ecology Center, Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
Int J Mol Sci. 2025 Apr 28;26(9):4193. doi: 10.3390/ijms26094193.
Despite centuries of research, metastatic cancer remains incurable due to resistance to 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 states, posing a challenge for clinical translation. We describe a convergent phenotype induced by chemotherapy where cells surviving chemotherapy have dysregulated iron homeostasis, regardless of initial cell type or chemotherapy used. Elevated labile iron levels are counteracted by NRF2 signaling, yet the resulting antioxidant programs do not alleviate the labile iron burden. 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.
尽管经过了数百年的研究，但由于对所有传统癌症治疗方法产生耐药性，转移性癌症仍然无法治愈。需要采用利用癌症中非增殖性弱点的替代策略来克服癌症复发。铁死亡是一种铁依赖性细胞死亡途径，在几种治疗耐药性癌症的情况下已显示出有前景的临床前活性。然而，铁死亡敏感性在不同组织类型和细胞状态之间高度可变，这给临床转化带来了挑战。我们描述了一种由化疗诱导的趋同表型，即无论初始细胞类型或使用的化疗药物如何，在化疗中存活的细胞都存在铁稳态失调。不稳定铁水平的升高通过NRF2信号传导得到抵消，但由此产生的抗氧化程序并不能减轻不稳定的铁负担。选择性抑制GPX4会导致存活细胞对铁死亡产生一致的敏感性，突出了对脂质过氧化防御的共同依赖。细胞铁失调是化疗耐药癌细胞的一个弱点，可以通过触发铁死亡来利用。
