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Nature. 2017 Nov 9;551(7679):247-250. doi: 10.1038/nature24297. Epub 2017 Nov 1.

Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition.

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Department of Microbiology and Immunology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, California 94143, USA.
UCSF Diabetes Center, University of California San Francisco, 513 Parnassus Avenue, San Francisco, California 94143, USA.
UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1450 3rd Street, San Francisco, California 94143, USA.
Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
DataSet Analysis LLC, 155 Jackson Street, San Francisco, California 94111, USA.
Cancer and Cell Biology Division, The Translational Genomics Research Institute, 445 N 5th Street, Phoenix, Arizona 85004, USA.
Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.


Acquired drug resistance prevents cancer therapies from achieving stable and complete responses. Emerging evidence implicates a key role for non-mutational drug resistance mechanisms underlying the survival of residual cancer 'persister' cells. 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 relapse. We previously found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival. 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.

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