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.
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We acknowledge technical support from the UCSF ES Cell Targeting Core and UCSF Preclinical Therapeutics Core. This work was supported by grants from the National Cancer Institute (NCI) of the National Institutes of Health (NIH) (Cancer Target Discovery and Development Network grant U01CA168370 to M.T.M. and F.M., U01CA217882 to M.T.M., U01CA176152 to S.L.S., U01CA168397 to M.E.B., and R01CA212767 to M.T.M.), Susan G. Komen for the Cure Postdoctoral Fellowship KG1101214 to M.J.H., and the Howard Hughes Medical Institute (S.L.S.).
Extended data figures
Extended data tables
This Supplementary Table contains RNAseq expression data (FPKM) and differential expression analysis for human RefSeq genes in BT474 parental and persister cells.
This Supplementary Table contains Ingenuity Pathway Analysis (IPA) “Functions” results derived from analysis of BT474 parental and persister cell RNAseq data.
This Supplementary Table contains Ingenuity Pathway Analysis (IPA) "Canonical Pathways" results derived from analysis of BT474 parental and persister cell RNAseq data.
This Supplementary Table contains Ingenuity Pathway Analysis (IPA) "Upstream Regulators" results derived from analysis of BT474 parental and persister cell RNAseq data.
About this article
Cell Chemical Biology (2019)