Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition
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Open Access
- 1 November 2017
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 551 (7679), 247-250
- https://doi.org/10.1038/nature24297
Abstract
Cancer persister cells, which survive cytotoxic treatments, are shown to be sensitive to inhibition of the lipid hydroperoxidase GPX4. During cancer treatment, tumours can become drug-resistant. In addition, so-called persister cells can emerge and form a reservoir from which resistant cancer cells can originate. Persister cells are no longer sensitive to some drugs, but Michael McManus and colleagues now report that they exist in a mesenchymal state in which they are selectively sensitive to the inhibition of the lipid hydroperoxidase GPX4. Targeting GPX4 could therefore represent a new therapeutic avenue to potentially prevent drug resistance. Acquired drug resistance prevents cancer therapies from achieving stable and complete responses1. Emerging evidence implicates a key role for non-mutational drug resistance mechanisms underlying the survival of residual cancer ‘persister’ cells2,3,4. The persister cell pool constitutes a reservoir from which drug-resistant tumours may emerge. Targeting persister cells therefore presents a therapeutic opportunity to impede tumour relapse5. We previously found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival6. Here we show that a similar therapy-resistant cell state underlies the behaviour of persister cells derived from a wide range of cancers and drug treatments. Consequently, we demonstrate that persister cells acquire a dependency on GPX4. Loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in mice. These findings suggest that targeting of GPX4 may represent a therapeutic strategy to prevent acquired drug resistance.This publication has 23 references indexed in Scilit:
- Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancerCancer Letters, 2016
- The cellular origins of drug resistance in cancerNature Medicine, 2016
- Ferroptosis as a p53-mediated activity during tumour suppressionNature, 2015
- Drug resistance to targeted therapies: Déjà vu all over againMolecular Oncology, 2014
- Ferrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease ModelsJournal of the American Chemical Society, 2014
- Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell DeathCell, 2012
- Gpx4 ablation in adult mice results in a lethal phenotype accompanied by neuronal loss in brainFree Radical Biology & Medicine, 2012
- Chemistry and biochemistry of lipid peroxidation productsFree Radical Research, 2010
- A systematic review of human antioxidant genesFrontiers in Bioscience-Landmark, 2009
- RAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channelsNature, 2007