Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway
Open accessAbstract
Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Mesenchymal-derived tissues have high sensitivity to ferroptosis.
“reports demonstrating high sensitivity to ferroptosis among mesenchymal-derived tissues (41)”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [41]
The Abstract reports that ferroptosis-inducing compounds were especially selective for cancer cell lines of mesenchymal origin, including sarcomas. The claim extends this finding from cancer cell lines to mesenchymal-derived tissues generally, which the paper does not establish. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCancer cells become susceptible to lipoxygenase/Fenton reaction-induced lipid-ROS damage and are dependent on GPX4 activity to maintain viability.
“While changes in the polyunsaturation of membrane lipids facilitate the invasive and motile cancer phenotype (9), cancer cells become susceptible to lipoxygenase/Fenton reaction–induced lipid-ROS damage and are dependent on the activity of GPX4 to maintain viability (6).”
From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [6]
The Abstract describes lipoxygenase-mediated lipid peroxidation and GPX4 protection against iron-mediated ferroptotic cell death; Extended Data Figure 10 shows that inhibiting lipoxygenases prevents death after GPX4 inhibition. The demonstrated GPX4 dependency is concentrated in therapy-resistant, high-mesenchymal cancer cells, not cancer cells generally. The copy describes iron-mediated reactions but does not specifically call them Fenton reactions. (LLM, conf=0.87)
Experimental — accuracy not yet measuredDuring multistage cell state transitions, cancer cells acquire a dependency on the ability to detoxify lipid peroxides.
“In particular, during multistage cell state transitions, cancer cells acquire a dependency on the ability to detoxify lipid peroxides (6).”
From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [6]
The paper’s main text (indexed under Abstract; page unavailable) reports that cancer cells acquiring therapy-resistant, high-mesenchymal states can become dependent on GPX4, which detoxifies lipid peroxides. It examines several cell-state transitions, but does not establish that those transitions are multistage or that the dependency arises during a defined sequence of stages. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMalignant cells with a mesenchymal phenotype reportedly acquire an accrued dependency on GPX4 activity, which can be exploited therapeutically.
“malignant cells with a mesenchymal phenotype (which are generally more resistant to treatment) reportedly acquire an accrued dependency on GPX4 activity, which can be exploited therapeutically [600].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [600]
Mesenchymal cells marked by high ZEB1 expression appear to be especially sensitive to GPX4 inhibition.
“Mesenchymal cells marked by high ZEB1 expression appear to be especially sensitive to GPX4 inhibition [119].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [119]
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 [165]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
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
Self-citationRegulation 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-citationImproved vectors and genome-wide libraries for CRISPR screening
Sanjana, N. E., Shalem, O., & Zhang, F. (2014) · Nature Methods · doi:10.1038/nmeth.3047 · Cited by 5,239 · see citing works
Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq
Tirosh, I., Izar, B., Prakadan, S. M., Wadsworth, M. H., Treacy, D., Trombetta, J. J., Rotem, A., Rodman, C., Lian, C., Murphy, G., et al. (2016) · Science · doi:10.1126/science.aad0501 · Cited by 4,944 · see citing works
Nieto, M. A., Huang, R. Y.-J., Jackson, R. A., & Thiery, J. P. (2016) · Cell · doi:10.1016/j.cell.2016.06.028 · Cited by 4,492 · see citing works
Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1
Barbie, D. A., Tamayo, P., Boehm, J. S., Kim, S. Y., Moody, S. E., Dunn, I. F., Schinzel, A. C., Sandy, P., Meylan, E., Scholl, C., et al. (2009) · Nature · doi:10.1038/nature08460 · Cited by 3,869 · see citing works
Self-citationCharacterization of Mammalian Selenoproteomes
Kryukov, G. V., Castellano, S., Novoselov, S. V., Lobanov, A. V., Zehtab, O., Guigó, R., & Gladyshev, V. N. (2003) · Science · doi:10.1126/science.1083516 · Cited by 2,353 · see citing works
Organoid Cultures Derived from Patients with Advanced Prostate Cancer
Gao, D., Vela, I., Sboner, A., Iaquinta, P. J., Karthaus, W. R., Gopalan, A., Dowling, C., Wanjala, J. N., Undvall, E. A., Arora, V. K., et al. (2014) · Cell · doi:10.1016/j.cell.2014.08.016 · Cited by 1,559 · see citing works
Self-citationZuris, J. A., Thompson, D. B., Shu, Y., Guilinger, J. P., Bessen, J. L., Hu, J. H., Maeder, M. L., Joung, J. K., Chen, Z.-Y., & Liu, D. R. (2015) · Nature Biotechnology · doi:10.1038/nbt.3081 · Cited by 1,460 · 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
Byers, L. A., Diao, L., Wang, J., Saintigny, P., Girard, L., Peyton, M., Shen, L., Fan, Y., Giri, U., Tumula, P. K., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1558 · Cited by 1,059 · see citing works
Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death
Dixon, S. J., Winter, G. E., Musavi, L. S., Lee, E. D., Snijder, B., Rebsamen, M., Superti-Furga, G., & Stockwell, B. R. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00245 · Cited by 1,043 · see citing works
Self-citationTaube, J. H., Herschkowitz, J. I., Komurov, K., Zhou, A. Y., Gupta, S. K., Yang, J., Hartwell, K. A., Önder, T. T., Gupta, P. B., Evans, K. W., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1004900107 · Cited by 1,041 · see citing works
Correlating chemical sensitivity and basal gene expression reveals mechanism of action
Rees, M. G., Seashore-Ludlow, B. A., Cheah, J. H., Adams, D., Price, E. V., Gill, S., Javaid, S., Coletti, M. E., Jones, V., Bodycombe, N. E., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1986 · Cited by 874 · see citing works
Self-citationHarnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset
Seashore-Ludlow, B., Rees, M. G., Cheah, J. H., Cokol, M., Price, E. V., Coletti, M. E., Jones, V., Bodycombe, N. E., Soule, C. K., Gould, J., et al. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0235 · Cited by 813 · see citing works
Self-citation<i>In vivo</i> Switching of Human Melanoma Cells between Proliferative and Invasive States
Hoek, K. S., Eichhoff, O. M., Schlegel, N. C., Döbbeling, U., Kobert, N., Schaerer, L., Hemmi, S., & Dummer, R. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-2491 · Cited by 743 · see citing works
Self-citationROCK Inhibitor and Feeder Cells Induce the Conditional Reprogramming of Epithelial Cells
Liu, X., Ory, V., Chapman, S., Yuan, H., Albanese, C., Kallakury, B., Timofeeva, O. A., Nealon, C., Dakic, A., Simic, V., et al. (2012) · The American Journal of Pathology · doi:10.1016/j.ajpath.2011.10.036 · Cited by 726 · see citing works
ZEB1: At the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance
Zhang, P., Sun, Y., & Ma, L. (2015) · Cell Cycle · doi:10.1080/15384101.2015.1006048 · Cited by 611 · see citing works
Systems biology and combination therapy in the quest for clinical efficacy
Fitzgerald, J. B., Schoeberl, B., Nielsen, U. B., & Sorger, P. K. (2006) · Nature Chemical Biology · doi:10.1038/nchembio817 · Cited by 570 · see citing works
Pathology and classification of ovarian tumors
Chen, V. W., Ruiz, B. A., Killeen, J. L., et al. (2003) · Cancer · doi:10.1002/cncr.11345 · Cited by 507 · see citing works
Ware, K. E., Hinz, T. K., Kleczko, E. K., Singleton, K. R., Marek, L. A., Helfrich, B., Cummings, C. T., Graham, D. K., Astling, D. P., Tan, A. C., et al. (2013) · Oncogenesis · doi:10.1038/oncsis.2013.4 · Cited by 250 · see citing works
Inhibition of selenoprotein synthesis by selenocysteine tRNA[Ser]Sec lacking isopentenyladenosine
Warner, G. J., Berry, M. J., Moustafa, M. E., Carlson, B. A., Hatfield, D. L., & Faust, J. R. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001280200 · Cited by 207 · see citing works
Gröger, C., Grubinger, M., Waldhoer, T., Vierlinger, K., & Mikulits, W. (2012) · PLoS ONE · doi:10.1371/journal.pone.0051136 · Cited by 184 · see citing works
Pathway Signature and Cellular Differentiation in Clear Cell Renal Cell Carcinoma
Tun, H. W., Marlow, L. A., Roemeling, C. A. V., Cooper, S. J., Kreinest, P. A., Wu, K. J., Luxon, B. A., Sinha, M., Anastasiadis, P. Z., & Copland, J. A. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010696 · Cited by 178 · 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
EMT or apoptosis: a decision for TGF-β
Song, J. (2007) · Cell Research · doi:10.1038/cr.2007.25 · Cited by 121 · see citing works
Javaid, S., Zhang, J., Anderssen, E., Black, J. C., Wittner, B. S., Tajima, K., Ting, D. T., Smolen, G. A., Zubrowski, M. J., Desai, R. N., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.11.034 · Cited by 119 · see citing works
Self-citationGubelmann, C., Schwalie, P. C., Raghav, S. K., Roeder, E., Challa, T. D., Kiehlmann, E., Waszak, S. M., Corsinotti, A., Udin, G., Holcombe, W., et al. (2014) · eLife · doi:10.7554/elife.03346 · Cited by 115 · see citing works
Cheng, P. F., Shakhova, O., Widmer, D. S., Eichhoff, O. M., Zingg, D., Frommel, S. C., Belloni, B., Raaijmakers, M. I., Goldinger, S. M., Santoro, R., et al. (2015) · Genome Biology · doi:10.1186/s13059-015-0594-4 · Cited by 100 · see citing works
Self-citationSnail transcription factor regulates neuroendocrine differentiation in LNCaP prostate cancer cells
McKeithen, D. N., Graham, T. R., Chung, L. W. K., & Odero‐Marah, V. (2010) · The Prostate · doi:10.1002/pros.21132 · Cited by 98 · see citing works
Learning from PD-1 Resistance: New Combination Strategies
Bu, X., Mahoney, K. M., & Freeman, G. J. (2016) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.04.008 · Cited by 71 · see citing works
Zeb1 affects epithelial cell adhesion by diverting glycosphingolipid metabolism
Mathow, D., Chessa, F., Rabionet, M., Kaden, S., Jennemann, R., Sandhoff, R., Gröne, H., & Feuerborn, A. (2015) · EMBO Reports · doi:10.15252/embr.201439333 · Cited by 64 · see citing works
Identification of a selective small molecule inhibitor of breast cancer stem cells
Germain, A. R., Carmody, L., Morgan, B., Fernández, C., Forbeck, E. M., Lewis, T. A., Nag, P. P., Ting, A., VerPlank, L., Feng, Y., et al. (2012) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2012.01.035 · Cited by 39 · see citing works
Self-citationHow long can folinic acid rescue be delayed after high‐dose methotrexate without toxicity?
Cohen, I. J., & Wolff, J. E. A. (2013) · Pediatric Blood & Cancer · doi:10.1002/pbc.24770 · Cited by 35 · see citing works
Dančík, V., Carrel, H. A., Bodycombe, N. E., Seiler, K. P., Fomina‐Yadlin, D., Kubicek, S., Hartwell, K. A., Shamji, A. F., Wagner, B. K., & Clemons, P. A. (2014) · SLAS DISCOVERY · doi:10.1177/1087057113520226 · Cited by 34 · see citing works
Self-citationEMT or apoptosis： a decision for TGF-β
Jianguo, & Song, S. (2007) · Acta Scientiarum Naturalium Universitatis Sunyatseni · Cited by 15 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease
Stockwell, B. R., Friedmann Angeli, J. P., Bayir, H., Bush, A. I., Conrad, M., Dixon, S. J., Fulda, S., Gascón, S., Hatzios, S. K., Kagan, V. E., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.021 · Cited by 7,695 · see citing works
Self-citationGalluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Self-citationThe 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
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
Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition
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., et al. (2017) · Nature · doi:10.1038/nature24297 · Cited by 1,799 · see citing works
Self-citationRole 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
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
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
Self-citationZou, 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-citationResolving 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
The emerging role of ferroptosis in inflammation
Sun, Y., Chen, P., Zhai, B., Zhang, M., Xiang, Y., Fang, J., Xu, S., Gao, Y., Chen, X., Sui, X., et al. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110108 · Cited by 739 · see citing works
Regulation of lipid peroxidation and ferroptosis in diverse species
Conrad, M., Kagan, V. E., Bayir, H., Pagnussat, G. C., Head, B., Traber, M. G., & Stockwell, B. R. (2018) · Genes & Development · doi:10.1101/gad.314674.118 · Cited by 544 · see citing works
Self-citationNon-redundant functions of EMT transcription factors
Stemmler, M. P., Eccles, R. L., Brabletz, S., & Brabletz, T. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0196-y · Cited by 524 · 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
Self-citationThe application of Ferroptosis in diseases
Qiu, Y., Cao, Y., Cao, W., Jia, Y., & Lu, N. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104919 · Cited by 415 · see citing works
Chen, P., Li, X., Zhang, R., Liu, S., Xiang, Y., Zhang, M., Chen, X., Pan, T., Yan, L., Feng, J., et al. (2020) · Theranostics · doi:10.7150/thno.44705 · Cited by 403 · 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
Self-citationNUPR1 is a critical repressor of ferroptosis
Liu, J., Song, X., Kuang, F., Zhang, Q., Xie, Y., Kang, R., Kroemer, G., & Tang, D. (2021) · Nature Communications · doi:10.1038/s41467-021-20904-2 · Cited by 290 · 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
Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer
Raoof, S., Mulford, I. J., Frisco-Cabanos, H., Nangia, V., Timonina, D., Labrot, E., Hafeez, N., Bilton, S. J., Drier, Y., Ji, F., et al. (2019) · Oncogene · doi:10.1038/s41388-019-0887-2 · Cited by 216 · see citing works
Self-citationThe 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
PDXNET Consortium, Woo, X. Y., EurOPDX Consortium, Giordano, J., Srivastava, A., Zhao, Z.-M., Lloyd, M. W., de Bruijn, R., Suh, Y.-S., Patidar, R., et al. (2021) · Nature Genetics · doi:10.1038/s41588-020-00750-6 · Cited by 190 · see citing works
Statins as Anticancer Agents in the Era of Precision Medicine
Longo, J., van Leeuwen, J. E., Elbaz, M., Branchard, E., & Penn, L. Z. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-1967 · Cited by 196 · see citing works
Chaudhary, 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
Raman-guided subcellular pharmaco-metabolomics for metastatic melanoma cells
Du, J., Su, Y., Qian, C., Yuan, D., Miao, K., Lee, D., Ng, A. H. C., Wijker, R. S., Ribas, A., Levine, R. D., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18376-x · Cited by 171 · see citing works
Iron in the Tumor Microenvironment-Connecting the Dots
Pfeifhofer-Obermair, C., Tymoszuk, P., Petzer, V., Weiss, G., & Nairz, M. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00549 · Cited by 151 · see citing works
Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability
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
Fujihara, K. M., Zhang, B. Z., Jackson, T. D., Ogunkola, M. O., Nijagal, B., Milne, J. V., Sallman, D. A., Ang, C.-S., Nikolic, I., Kearney, C. J., et al. (2022) · Science Advances · doi:10.1126/sciadv.abm9427 · Cited by 103 · see citing works
“Hematological and neurological toxicities, as well as impaired renal function, have been reported in patients receiving eprene-tapopt ( 3 , 4 ), which is in line with reports demonstrating high sensitivity to ferroptosis among mesenchymal-derived tissues ( 41 ).”
Selective ferroptosis vulnerability due to familial Alzheimer’s disease presenilin mutations
Greenough, M. A., Lane, D. J. R., Balez, R., Anastacio, H. T. D., Zeng, Z., Ganio, K., McDevitt, C. A., Acevedo, K., Belaidi, A. A., Koistinaho, J., et al. (2022) · Cell Death & Differentiation · doi:10.1038/s41418-022-01003-1 · Cited by 102 · see citing works
Hoerner, C. R., Chen, V. J., & Fan, A. C. (2019) · Kidney Cancer · doi:10.3233/kca-180043 · Cited by 68 · 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
Taking advantage of drug resistance, a new approach in the war on cancer
Wang, L., & Bernards, R. (2018) · Frontiers of Medicine · doi:10.1007/s11684-018-0647-7 · Cited by 53 · see citing works
Fujihara, K. M., Corrales Benitez, M., Cabalag, C. S., Zhang, B. Z., Ko, H. S., Liu, D. S., Simpson, K. J., Haupt, Y., Lipton, L., Haupt, S., et al. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-21-0067 · Cited by 48 · see citing works
Unveiling ferroptosis as a promising therapeutic avenue for colorectal cancer and colitis treatment
Kao, A. T., Cabanlong, C. V., Padilla, K., & Xue, X. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.05.025 · Cited by 30 · see citing works
Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis
More, S., Bonnereau, J., Wouters, D., Spotbeen, X., Karras, P., Rizzollo, F., Killian, T., Venken, T., Naulaerts, S., Vervoort, E., et al. (2024) · Science Advances · doi:10.1126/sciadv.adp6164 · Cited by 25 · see citing works
Self-citationExploring 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
- 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., Viswanathan, S. R., Chattopadhyay, S., Tamayo, P., Yang, W. S., Rees, M. G., Chen, S., Boskovic, Z. V., Javaid, S., Huang, C., Wu, X., Tseng, Y.-Y., Roider, E. M., Gao, D., Cleary, J. M., Wolpin, B. M., Mesirov, J. P., Haber, D. A., Engelman, J. A., Boehm, J. S., Kotz, J. D., Hon, C. S., Chen, Y., Hahn, W. C., Levesque, M. P., Doench, J. G., Berens, M. E., Shamji, A. F., Clemons, P. A., Stockwell, B. R., & Schreiber, S. L.
- Affiliations
- Broad Institute (US)
- Translational Genomics Research Institute (US)
- University of Zurich (CH)
- Memorial Sloan Kettering Cancer Center (US)
- Harvard University (US)
- St. John's University (US)
- Massachusetts General Hospital (US)
- Dana-Farber Cancer Institute (US)
- Howard Hughes Medical Institute (US)
- Columbia University (US)
- Corresponding author
- Schreiber, Stuart L.
- ORCID
- Viswanathan, Vasanthi S.
- Ryan, Matthew J.
- Dhruv, Harshil D.
- Eichhoff, Ossia M.
- Seashore-Ludlow, Brinton
- Kaffenberger, Samuel D.
- Eaton, John K.
- Aguirre, Andrew J.
- Viswanathan, Srinivas R.
- Chattopadhyay, Shrikanta
- Tamayo, Pablo
- Yang, Wan Seok
- Rees, Matthew G.
- Wu, Xiaoyun
- Tseng, Yuen-Yi
- Roider, Elisabeth M.
- Gao, Dong
- Cleary, James M.
- Wolpin, Brian M.
- Mesirov, Jill P.
- Haber, Daniel A.
- Engelman, Jeffrey A.
- Boehm, Jesse S.
- Kotz, Joanne D.
- Chen, Yu
- Hahn, William C.
- Levesque, Mitchell P.
- Doench, John G.
- Berens, Michael E.
- Clemons, Paul A.
- Stockwell, Brent R.
- Schreiber, Stuart L.
- Venue
- Nature
- Published
- 2017-07
- Volume
- 547
- Issue
- 7664
- Pages
- 453-457
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5667900
- OpenAlex
- W2727828415
- Cited by
- 2,011
- References
- 36
- Citations by year
- 2026: 231 · 2025: 280 · 2024: 345 · 2023: 300 · 2022: 261 · 2021: 230 · 2020: 159 · 2019: 115 · 2018: 64 · 2017: 18 · 2016: 3 · 2015: 1 · 2014: 1
- FWCI
- 80.76
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- 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 Institutes of Health (UL1TR001102)
- National Cancer Institute (R35CA209896, R01CA208100, U24CA194107, R01CA154480, R01CA097061, U01CA217848, U01CA176152, R01CA161061, U01CA168397, R01CA121941, U01CA176058, U01CA199253, K08CA218420, P30CA008748, R01CA129933, P50CA092629, R01CA193837)
- National Institute of General Medical Sciences (R01GM085081, R01GM038627, R01GM074024)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK043351)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- treatment resistance, cancer cell states, mesenchymal phenotype, ferroptosis, GPX4, lipid peroxidation, lipoxygenase, lipid metabolism, ZEB1, epithelial-mesenchymal transition, TGF-beta, neuroendocrine transdifferentiation, sarcoma, organoids, drug repurposing
- MeSH terms
- Zinc Finger E-box-Binding Homeobox 1, Phospholipid Hydroperoxide Glutathione Peroxidase, Glutathione Peroxidase, Humans, Iron, Lipid Peroxides, Male, Melanoma, Mesoderm, Neoplasms, Prostatic Neoplasms, Reproducibility of Results, Lipid Peroxidation, Cadherins, Cell Death, Drug Resistance, Neoplasm, Cell Lineage, Proteomics, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Cell Transdifferentiation, Epithelial-Mesenchymal Transition
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
