Letter | Published:

Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition

Nature volume 551, pages 247250 (09 November 2017) | Download Citation

Abstract

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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Acknowledgements

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.).

Author information

Affiliations

  1. Department of Microbiology and Immunology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, California 94143, USA.

    • Matthew J. Hangauer
    •  & Michael T. McManus
  2. UCSF Diabetes Center, University of California San Francisco, 513 Parnassus Avenue, San Francisco, California 94143, USA.

    • Matthew J. Hangauer
    •  & Michael T. McManus
  3. UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1450 3rd Street, San Francisco, California 94143, USA.

    • Matthew J. Hangauer
    • , Dhruv Bole
    • , Jacqueline Galeas
    •  & Frank McCormick
  4. Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.

    • Vasanthi S. Viswanathan
    • , Matthew J. Ryan
    • , John K. Eaton
    •  & Stuart L. Schreiber
  5. DataSet Analysis LLC, 155 Jackson Street, San Francisco, California 94111, USA.

    • Alexandre Matov
  6. Cancer and Cell Biology Division, The Translational Genomics Research Institute, 445 N 5th Street, Phoenix, Arizona 85004, USA.

    • Harshil D. Dhruv
    •  & Michael E. Berens
  7. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.

    • Stuart L. Schreiber
  8. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.

    • Stuart L. Schreiber

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Contributions

M.T.M. and F.M. directed the project; M.J.H., V.S.V., S.L.S., F.M. and M.T.M. wrote the manuscript; M.J.H. performed chemical screens, RNA-seq analysis, and all cell culture experiments except V.S.V. and M.J.R. performed Kuramochi cell GPX4 inhibitor assays, D.B. assisted with ROS, glutathione and NADPH assays, and J.G. performed western blots; M.J.H. directed CRISPR editing of A375 cells and in vivo experiments that were performed at UCSF core facilities; V.S.V. and J.K.E. contributed reagents; A.M., H.D.D. and M.E.B. provided advice and project support.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Frank McCormick or Michael T. McManus.

Reviewer Information Nature thanks N. Chandel and P. Vandenabeele and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains the raw western blot files for Extended Data Figure 1g.

  2. 2.

    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Table 1

    This Supplementary Table contains RNAseq expression data (FPKM) and differential expression analysis for human RefSeq genes in BT474 parental and persister cells.

  2. 2.

    Supplementary Table 2

    This Supplementary Table contains Ingenuity Pathway Analysis (IPA) “Functions” results derived from analysis of BT474 parental and persister cell RNAseq data.

  3. 3.

    Supplementary Table 3

    This Supplementary Table contains Ingenuity Pathway Analysis (IPA) "Canonical Pathways" results derived from analysis of BT474 parental and persister cell RNAseq data.

  4. 4.

    Supplementary Table 4

    This Supplementary Table contains Ingenuity Pathway Analysis (IPA) "Upstream Regulators" results derived from analysis of BT474 parental and persister cell RNAseq data.

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DOI

https://doi.org/10.1038/nature24297

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