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Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition
Acquired drug resistance prevents cancer therapies from achieving stable and complete responses.(1) Emerging evidence implicates a key role for nonmutational drug resistance mechanisms underlying the survival of residual cancer “persister” cells.(2-4) The persister cell pool constitutes a reservoir...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933935/ https://www.ncbi.nlm.nih.gov/pubmed/29088702 http://dx.doi.org/10.1038/nature24297 |
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author | Hangauer, Matthew J. Viswanathan, Vasanthi S. Ryan, Matthew J. Bole, Dhruv Eaton, John K. Matov, Alexandre Galeas, Jacqueline Dhruv, Harshil D. Berens, Michael E. Schreiber, Stuart L. McCormick, Frank McManus, Michael T. |
author_facet | Hangauer, Matthew J. Viswanathan, Vasanthi S. Ryan, Matthew J. Bole, Dhruv Eaton, John K. Matov, Alexandre Galeas, Jacqueline Dhruv, Harshil D. Berens, Michael E. Schreiber, Stuart L. McCormick, Frank McManus, Michael T. |
author_sort | Hangauer, Matthew J. |
collection | PubMed |
description | Acquired drug resistance prevents cancer therapies from achieving stable and complete responses.(1) Emerging evidence implicates a key role for nonmutational drug resistance mechanisms underlying the survival of residual cancer “persister” cells.(2-4) 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 relapse.(5) In an earlier report, we found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival.(6) Here, we describe the discovery that a similar therapy-resistant cell state underlies the behavior of persister cells derived from a wide range of cancers and drug treatments. Consequently, we show that persister cells acquire a dependency on GPX4. We demonstrate that loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in vivo. These findings support targeting GPX4 as a therapeutic strategy to prevent acquired drug resistance. |
format | Online Article Text |
id | pubmed-5933935 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
record_format | MEDLINE/PubMed |
spelling | pubmed-59339352018-05-03 Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition Hangauer, Matthew J. Viswanathan, Vasanthi S. Ryan, Matthew J. Bole, Dhruv Eaton, John K. Matov, Alexandre Galeas, Jacqueline Dhruv, Harshil D. Berens, Michael E. Schreiber, Stuart L. McCormick, Frank McManus, Michael T. Nature Article Acquired drug resistance prevents cancer therapies from achieving stable and complete responses.(1) Emerging evidence implicates a key role for nonmutational drug resistance mechanisms underlying the survival of residual cancer “persister” cells.(2-4) 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 relapse.(5) In an earlier report, we found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival.(6) Here, we describe the discovery that a similar therapy-resistant cell state underlies the behavior of persister cells derived from a wide range of cancers and drug treatments. Consequently, we show that persister cells acquire a dependency on GPX4. We demonstrate that loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in vivo. These findings support targeting GPX4 as a therapeutic strategy to prevent acquired drug resistance. 2017-11-01 2017-11-09 /pmc/articles/PMC5933935/ /pubmed/29088702 http://dx.doi.org/10.1038/nature24297 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Hangauer, Matthew J. Viswanathan, Vasanthi S. Ryan, Matthew J. Bole, Dhruv Eaton, John K. Matov, Alexandre Galeas, Jacqueline Dhruv, Harshil D. Berens, Michael E. Schreiber, Stuart L. McCormick, Frank McManus, Michael T. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition |
title | Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition |
title_full | Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition |
title_fullStr | Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition |
title_full_unstemmed | Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition |
title_short | Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition |
title_sort | drug-tolerant persister cancer cells are vulnerable to gpx4 inhibition |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933935/ https://www.ncbi.nlm.nih.gov/pubmed/29088702 http://dx.doi.org/10.1038/nature24297 |
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