Blog
About

7
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          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.

          Related collections

          Most cited references 25

          • Record: found
          • Abstract: found
          • Article: not found

          Ferroptosis: an iron-dependent form of nonapoptotic cell death.

          Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations.

            Accumulating evidence implicates heterogeneity within cancer cell populations in the response to stressful exposures, including drug treatments. While modeling the acute response to various anticancer agents in drug-sensitive human tumor cell lines, we consistently detected a small subpopulation of reversibly "drug-tolerant" cells. These cells demonstrate >100-fold reduced drug sensitivity and maintain viability via engagement of IGF-1 receptor signaling and an altered chromatin state that requires the histone demethylase RBP2/KDM5A/Jarid1A. This drug-tolerant phenotype is transiently acquired and relinquished at low frequency by individual cells within the population, implicating the dynamic regulation of phenotypic heterogeneity in drug tolerance. The drug-tolerant subpopulation can be selectively ablated by treatment with IGF-1 receptor inhibitors or chromatin-modifying agents, potentially yielding a therapeutic opportunity. Together, these findings suggest that cancer cell populations employ a dynamic survival strategy in which individual cells transiently assume a reversibly drug-tolerant state to protect the population from eradication by potentially lethal exposures. Copyright 2010 Elsevier Inc. All rights reserved.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Regulation of ferroptotic cancer cell death by GPX4.

              Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death. Copyright © 2014 Elsevier Inc. All rights reserved.
                Bookmark

                Author and article information

                Contributors
                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                21 September 2017
                01 November 2017
                09 November 2017
                03 May 2018
                : 551
                : 7679
                : 247-250
                Affiliations
                Department of Microbiology and Immunology and 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
                Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, 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
                Data Set Analysis LLC, 155 Jackson Street, San Francisco, California 94111, USA
                UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1450 3rd Street, San Francisco, California 94143, USA
                Cancer and Cell Biology Division, The Translational Genomics Research Institute, 445 N 5th Street, Phoenix, Arizona 85004, USA
                Cancer and Cell Biology Division, The Translational Genomics Research Institute, 445 N 5th Street, Phoenix, Arizona 85004, USA
                Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA; Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
                UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1450 3rd Street, San Francisco, California 94143, USA
                Department of Microbiology and Immunology and UCSF Diabetes Center, University of California San Francisco, 513 Parnassus Avenue, San Francisco, California 94143, USA
                Author notes
                Correspondence and request for materials should be sent to M.T.M. ( michael.mcmanus@ 123456ucsf.edu ) or F.M. ( frank.mccormick@ 123456ucsf.edu )
                Article
                NIHMS907407
                10.1038/nature24297
                5933935
                29088702

                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

                Categories
                Article

                Uncategorized

                Comments

                Comment on this article