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Cancer persister cells that survive initial chemotherapy treatment can be killed by inducing ferroptosis, a form of programmed cell death, but cells surviving topoisomerase inhibitors develop resistance to ferroptosis through a novel protective mechanism. These resistant persisters activate NMDA receptors (typically found in brain cells) which trigger a calcium-dependent signaling pathway involving AKT and NFE2L2 that protects cells from oxidative stress and ferroptosis. Blocking both the standard Xc- antiporter pathway and this newly identified NMDAR/NFE2L2 axis together can overcome this resistance and eliminate persister cells.
Why it matters
This research identifies a previously unknown survival mechanism in chemotherapy-resistant cancer cells and suggests that combining standard cancer drugs with NMDAR inhibitors could prevent treatment resistance and improve outcomes for cancer patients. The findings are particularly relevant for colorectal cancer and other tumors treated with topoisomerase inhibitors.
Understand the Science
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Upon treatment, cancer cells engage non-genetic adaptations, including tolerance and subsequent persistence, to survive therapy. Eliciting programmed cancer cell death in these persister cells (PCs) remains a primary goal in oncology. We found that ferroptosis is the programmed cell death mechanism most deregulated in persisters by some of the most widely used therapeutic regimens, including platinum-based therapies, which combined with ferroptosis inducers ablate persister colorectal cancer cells. Conversely, persisters emerging from topoisomerase inhibitor regimens withstand ferroptosis and ferroptotic inducers, increasing instead intracellular iron concentration. We found that topoisomerase inhibitors trigger the Xc- antiporter axis (via SLC7A11 and CD44) increasing both intracellular cystine, to activate GPX4, and extracellular glutamate. Glutamate then engages the NMDA receptors (NMDARs), which are essential in neurotransmission but recently reported to be deregulated also in cancer cells. In PCs, NMDARs stimulate intracellular Ca2+ uptake and trigger the AKT/NFE2L2 axis, thereby engaging a cytoprotective program to cope with oxidative stress. Furthermore, we found that NFE2L2 increases the distance between the endoplasmic reticulum and mitochondria while reducing mitochondrial ROS in PCs. The synergistic inhibition of both the standard (Xc- antiporter) and this novel NMDAR/NFE2L2 axis resensitizes PCs to ferroptosis. These data provide new opportunities to improve the efficacy of widely used therapeutic regimens.
Source: Cancer persister cells activate NMDARs to survive ferroptosis