Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition
Open accessAbstract
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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Cancer cells use non-mutational adaptations to resist a wide variety of single drugs or drug combinations, including inhibitors targeting BRAF, MEK, EGFR, and KRAS.
“Cancer cells use non-mutational adaptations to resist a wide variety of single drugs or drug combinations, including inhibitors targeting BRAF, MEK, EGFR, and KRAS [118,119].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [119]
The Abstract describes reversible, nonmutational survival after targeted therapy, and Methods > Persister cell derivation and treatments documents persisters after single drugs and combinations targeting BRAF, MEK, or EGFR. The passages do not document resistance to a KRAS-targeting inhibitor, so that example is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSome studies indicate that drug-tolerant persister populations or cancer cells primed to persist exist even prior to treatment.
“Some studies indicate that drug-tolerant persister populations or cancer cells that are primed to persist exist even prior to treatment [40,43,60,61].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [40]
Therapy-resistant and drug-tolerant tumor cells are prone to ferroptosis.
“Interestingly, especially therapy-resistant and drug-tolerant tumor cells are prone to ferroptosis [164,165].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [164]
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Cites
Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.042 · Cited by 18,691 · see citing works
Regulation of Ferroptotic Cancer Cell Death by GPX4
Yang, W. S., SriRamaratnam, R., Welsch, M. E., Shimada, K., Skouta, R., Viswanathan, V. S., Cheah, J. H., Clemons, P. A., Shamji, A. F., Clish, C. B., et al. (2014) · Cell · doi:10.1016/j.cell.2013.12.010 · Cited by 7,713 · see citing works
Self-citationInactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice
Friedmann Angeli, J. P., Schneider, M., Proneth, B., Tyurina, Y. Y., Tyurin, V. A., Hammond, V. J., Herbach, N., Aichler, M., Walch, A., Eggenhofer, E., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3064 · Cited by 3,732 · see citing works
Ferroptosis as a p53-mediated activity during tumour suppression
Jiang, L., Kon, N., Li, T., Wang, S.-J., Su, T., Hibshoosh, H., Baer, R., & Gu, W. (2015) · Nature · doi:10.1038/nature14344 · Cited by 3,398 · see citing works
Ferroptosis: Death by Lipid Peroxidation
Yang, W. S., & Stockwell, B. R. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.10.014 · Cited by 3,088 · see citing works
A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell Subpopulations
Sharma, S. V., Lee, D. Y., Li, B., Quinlan, M. P., Takahashi, F., Maheswaran, S., McDermott, U., Azizian, N., Zou, L., Fischbach, M. A., et al. (2010) · Cell · doi:10.1016/j.cell.2010.02.027 · Cited by 2,770 · see citing works
Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway
Viswanathan, V. S., Ryan, M. J., Dhruv, H. D., Gill, S., Eichhoff, O. M., Seashore-Ludlow, B., Kaffenberger, S. D., Eaton, J. K., Shimada, K., Aguirre, A. J., et al. (2017) · Nature · doi:10.1038/nature23007 · Cited by 2,011 · see citing works
Self-citationRAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels
Yagoda, N., von Rechenberg, M., Zaganjor, E., Bauer, A. J., Yang, W. S., Fridman, D. J., Wolpaw, A. J., Smukste, I., Peltier, J. M., Boniface, J. J., et al. (2007) · Nature · doi:10.1038/nature05859 · Cited by 1,631 · see citing works
Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance
Shaffer, S. M., Dunagin, M. C., Torborg, S. R., Torre, E. A., Emert, B., Krepler, C., Beqiri, M., Sproesser, K., Brafford, P. A., Xiao, M., et al. (2017) · Nature · doi:10.1038/nature22794 · Cited by 1,218 · see citing works
Ferrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease Models
Skouta, R., Dixon, S. J., Wang, J., Dunn, D. E., Orman, M., Shimada, K., Rosenberg, P. A., Lo, D. C., Weinberg, J. M., Linkermann, A., et al. (2014) · Journal of the American Chemical Society · doi:10.1021/ja411006a · Cited by 1,146 · see citing works
Hata, A. N., Niederst, M. J., Archibald, H. L., Gomez-Caraballo, M., Siddiqui, F. M., Mulvey, H. E., Maruvka, Y. E., Ji, F., Bhang, H.-E. C., Krishnamurthy Radhakrishna, V., et al. (2016) · Nature Medicine · doi:10.1038/nm.4040 · Cited by 985 · see citing works
Chemistry and biochemistry of lipid peroxidation products
Guéraud, F., Atalay, M., Bresgen, N., Gašparović, A. Č., Eckl, P., Laurence Therese, H. U. C., Jouanin, I., Siems, W., & Uchida, K. (2010) · Free Radical Research · doi:10.3109/10715762.2010.498477 · Cited by 556 · see citing works
Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer
Roh, J., Kim, E. H., Jang, H. J., Park, J. Y., & Shin, D. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.07.035 · Cited by 375 · see citing works
Raha, D., Wilson, T. R., Peng, J., Peterson, D., Yue, P., Evangelista, M., Wilson, C., Merchant, M., & Settleman, J. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-3456 · Cited by 307 · see citing works
Shimada, K., Hayano, M., Pagano, N. C., & Stockwell, B. R. (2016) · Cell chemical biology · doi:10.1016/j.chembiol.2015.11.016 · Cited by 300 · see citing works
Gpx4 ablation in adult mice results in a lethal phenotype accompanied by neuronal loss in brain
Yoo, S.-E., Chen, L., Na, R., Liu, Y., Rios, C. I., Remmen, H. V., Richardson, A. G., & Ran, Q. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.02.043 · Cited by 250 · see citing works
Drug resistance to targeted therapies: Déjà vu all over again
Groenendijk, F. H., & Bernards, R. (2014) · Molecular Oncology · doi:10.1016/j.molonc.2014.05.004 · Cited by 211 · see citing works
Epithelial-to-Mesenchymal Transition Rewires the Molecular Path to PI3K-Dependent Proliferation
Salt, M. B., Bandyopadhyay, S., & McCormick, F. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0520 · Cited by 124 · see citing works
Self-citationFan, W., Tang, Z., Yin, L., Morrison, B., Hafez-Khayyata, S., Fu, P., Huang, H., Bagai, R. K., Jiang, S., Kresak, A. M., et al. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-2668 · Cited by 83 · see citing works
The cellular origins of drug resistance in cancer
Oxnard, G. R. (2016) · Nature Medicine · doi:10.1038/nm.4058 · Cited by 62 · see citing works
A systematic review of human antioxidant genes
Daniel, P. G. (2009) · Frontiers in bioscience · doi:10.2741/3541 · Cited by 59 · see citing works
Kriska, T., Pilat, A. K., Schmitt, J. C., & Girotti, A. W. (2010) · Journal of Lipid Research · doi:10.1194/jlr.m008342 · Cited by 30 · see citing works
Binding-induced, turn-on fluorescence of the EGFR/ERBB kinase inhibitor, lapatinib
Wilson, J. N., Liu, W., Brown, A. S., et al. (2015) · Organic & Biomolecular Chemistry · doi:10.1039/c5ob00239g · Cited by 29 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis
Bersuker, K., Hendricks, J. M., Li, Z., Magtanong, L., Ford, B., Tang, P. H., Roberts, M. A., Tong, B., Maimone, T. J., Zoncu, R., et al. (2019) · Nature · doi:10.1038/s41586-019-1705-2 · Cited by 3,703 · see citing works
Metabolic reprogramming and cancer progression
Faubert, B., Solmonson, A., & DeBerardinis, R. J. (2020) · Science · doi:10.1126/science.aaw5473 · Cited by 2,740 · see citing works
Targeting Ferroptosis as a Vulnerability in Cancer
Lei, G., Zhuang, L., & Gan, B. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-022-00459-0 · Cited by 2,252 · see citing works
Role of GPX4 in ferroptosis and its pharmacological implication
Seibt, T. M., Proneth, B., & Conrad, M. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.09.014 · Cited by 1,520 · see citing works
Ferroptosis: Mechanisms and links with diseases
Yan, H.-F., Zou, T., Tuo, Q.-Z., Xu, S., Li, H., Belaidi, A. A., & Lei, P. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00428-9 · Cited by 1,471 · see citing works
Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens
Behan, F. M., Iorio, F., Picco, G., Gonçalves, E., Beaver, C. M., Migliardi, G., Santos, R., Rao, Y., Sassi, F., Pinnelli, M., et al. (2019) · Nature · doi:10.1038/s41586-019-1103-9 · Cited by 1,338 · see citing works
Intercellular interaction dictates cancer cell ferroptosis via NF2–YAP signalling
Wu, J., Minikes, A. M., Gao, M., Bian, H., Li, Y., Stockwell, B. R., Chen, Z.-N., & Jiang, X. (2019) · Nature · doi:10.1038/s41586-019-1426-6 · Cited by 1,110 · see citing works
Zou, Y., Palte, M. J., Deik, A. A., Li, H., Eaton, J. K., Wang, W., Tseng, Y.-Y., Deasy, R., Kost-Alimova, M., Dančík, V., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09277-9 · Cited by 887 · see citing works
Self-citationSenescence and cancer — role and therapeutic opportunities
Schmitt, C. A., Wang, B., & Demaria, M. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00668-4 · Cited by 794 · see citing works
Resolving the Role of Lipoxygenases in the Initiation and Execution of Ferroptosis
Shah, R., Shchepinov, M. S., & Pratt, D. A. (2018) · ACS Central Science · doi:10.1021/acscentsci.7b00589 · Cited by 782 · see citing works
Colorectal Cancer Cells Enter a Diapause-like DTP State to Survive Chemotherapy
Rehman, S. K., Haynes, J., Collignon, E., Brown, K. R., Wang, Y., Nixon, A. M. L., Bruce, J. P., Wintersinger, J. A., Singh Mer, A., Lo, E. B. L., et al. (2021) · Cell · doi:10.1016/j.cell.2020.11.018 · Cited by 495 · see citing works
Pan-cancer single-cell RNA-seq identifies recurring programs of cellular heterogeneity
Kinker, G. S., Greenwald, A. C., Tal, R., Orlova, Z., Cuoco, M. S., McFarland, J. M., Warren, A., Rodman, C., Roth, J. A., Bender, S. A., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-00726-6 · Cited by 445 · see citing works
The chemistry and biology of ferroptosis
Stockwell, B. R., & Jiang, X. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2020.03.013 · Cited by 429 · see citing works
Phototherapy in cancer treatment: strategies and challenges
Cai, Y., Chai, T., Nguyen, W., Liu, J., Xiao, E., Ran, X., Ran, Y., Du, D., Chen, W., & Chen, X. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02140-y · Cited by 453 · see citing works
Lipid Metabolism and Ferroptosis
Lee, J.-Y., Kim, W. K., Bae, K.-H., Lee, S. C., & Lee, E.-W. (2021) · Biology · doi:10.3390/biology10030184 · Cited by 374 · see citing works
iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4
Chen, D., Chu, B., Yang, X., Liu, Z., Jin, Y., Kon, N., Rabadan, R., Jiang, X., Stockwell, B. R., & Gu, W. (2021) · Nature Communications · doi:10.1038/s41467-021-23902-6 · Cited by 348 · see citing works
Mukhopadhyay, S., Goswami, D., Adiseshaiah, P. P., Burgan, W., Yi, M., Guerin, T. M., Kozlov, S. V., Nissley, D. V., & McCormick, F. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-1363 · Cited by 279 · see citing works
Self-citationDietary lipids fuel GPX4-restricted enteritis resembling Crohn’s disease
Mayr, L., Grabherr, F., Schwärzler, J., Reitmeier, I., Sommer, F., Gehmacher, T., Niederreiter, L., He, G.-W., Ruder, B., Kunz, K. T. R., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15646-6 · Cited by 292 · see citing works
Iron as a central player and promising target in cancer progression
Jung, M., Mertens, C., Tomat, E., & Brüne, B. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20020273 · Cited by 268 · see citing works
Tumor cell plasticity in targeted therapy-induced resistance: Mechanisms and new strategies
Shi, Z.-D., Pang, K., Wu, Z.-X., Dong, Y., Hao, L., Qin, J.-X., Wang, W., Chen, Z.-S., & Han, C.-H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01383-x · Cited by 256 · see citing works
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The Diverse Functions of Non-Essential Amino Acids in Cancer
Choi, B.-H., & Coloff, J. L. (2019) · Cancers · doi:10.3390/cancers11050675 · Cited by 213 · see citing works
Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer
Cabanos, H. F., & Hata, A. N. (2021) · Cancers · doi:10.3390/cancers13112666 · Cited by 189 · see citing works
Cancer drug-tolerant persister cells: from biological questions to clinical opportunities
Russo, M., Chen, M., Mariella, E., Peng, H., Rehman, S. K., Sancho, E., Sogari, A., Toh, T. S., Balaban, N. Q., Batlle, E., et al. (2024) · Nature Reviews Cancer · doi:10.1038/s41568-024-00737-z · Cited by 210 · see citing works
Self-citationChaudhary, N., Choudhary, B. S., Shah, S. G., Khapare, N., Dwivedi, N., Gaikwad, A., Joshi, N., Raichanna, J., Basu, S., Gurjar, M., et al. (2021) · International Journal of Cancer · doi:10.1002/ijc.33711 · Cited by 185 · see citing works
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Sadida, H. Q., Abdulla, A., Marzooqi, S. A., Hashem, S., Macha, M. A., Akil, A. S. A.-S., & Bhat, A. A. (2024) · Translational Oncology · doi:10.1016/j.tranon.2023.101821 · Cited by 151 · see citing works
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Li, Z., Ferguson, L., Deol, K. K., Roberts, M. A., Magtanong, L., Hendricks, J. M., Mousa, G. A., Kilinc, S., Schaefer, K., Wells, J. A., et al. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-01033-3 · Cited by 134 · see citing works
Zhang, X., Ma, Y., Ma, J., Yang, L., Song, Q., Wang, H., & Lv, G. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.913669 · Cited by 57 · see citing works
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Ash, L. J., Busia-Bourdain, O., Okpattah, D., Kamel, A., Liberchuk, A., & Wolfe, A. L. (2024) · Current Oncology · doi:10.3390/curroncol31040150 · Cited by 59 · see citing works
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Wang, L., & Bernards, R. (2018) · Frontiers of Medicine · doi:10.1007/s11684-018-0647-7 · Cited by 53 · see citing works
Zhang, H., Zhu, S., Zhou, H., Li, R., Xia, X., & Xiong, H. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1098357 · Cited by 46 · see citing works
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Lee, W.-K., & Thévenod, F. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.01.044 · Cited by 28 · see citing works
El Meouche, I., Jain, P., Jolly, M. K., & Capp, J.-P. (2024) · Translational Oncology · doi:10.1016/j.tranon.2024.102069 · Cited by 22 · see citing works
Exploring and bypassing resistance to targeted therapies in colorectal cancer
Favier, S., Xiong, W., Chalabi-Dchar, M., Chettab, K., Piercey, O., Wu, T., Fenouil, T., Albaret, M.-A., Jordheim, L. P., Diaz, J.-J., et al. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118741 · Cited by 12 · see citing works
- Authors
- Hangauer, M. J., Viswanathan, V. S., Ryan, M. J., Bole, D., Eaton, J. K., Matov, A., Galeas, J., Dhruv, H. D., Berens, M. E., Schreiber, S. L., McCormick, F., & McManus, M. T.
- Affiliations
- University of California, San Francisco (US)
- Broad Institute (US)
- Translational Genomics Research Institute (US)
- Corresponding author
- McCormick, Frank
- McManus, Michael T.
- ORCID
- Venue
- Nature
- Published
- 2017-11
- Volume
- 551
- Issue
- 7679
- Pages
- 247-250
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5933935
- OpenAlex
- W2767055857
- Cited by
- 1,799
- References
- 23
- Citations by year
- 2026: 255 · 2025: 282 · 2024: 272 · 2023: 263 · 2022: 222 · 2021: 187 · 2020: 154 · 2019: 96 · 2018: 54 · 2017: 6 · 2016: 3 · 2015: 1 · 2014: 1 · 2012: 1
- FWCI
- 70.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R01CA212767, U01CA217848, U01CA176152, U01CA217882, U01CA168397, U01CA168370)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- drug-tolerant persister cells, GPX4 inhibition, ferroptosis, acquired drug resistance, tumor recurrence, cancer stem cells, cancer therapy resistance
- MeSH terms
- Phospholipid Hydroperoxide Glutathione Peroxidase, Animals, Antioxidants, Drug Evaluation, Preclinical, Female, Glutathione Peroxidase, Humans, Iron, Male, Mesoderm, Neoplasms, Recurrence, Apoptosis, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Mice, Molecular Targeted Therapy
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