Imetelstat is a first-in-class telomerase inhibitor with efficacy in a number of blood cancers. Intriguingly, telomere lengths do not predict patient responses to imetelstat. We now show that imetelstat causes cell death by a mechanism that involves two regulators of fatty acid metabolism (FADS2 and ACSL4), driving excessive lipid reactive oxygen species formation and ferroptosis.
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References
Tefferi, A. et al. A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. N. Engl. J. Med. 373, 908–919 (2015). This paper reports clinical efficacy of imetelstat in patients with myelofibrosis.
Steensma, D. P. et al. Imetelstat achieves meaningful and durable transfusion independence in high transfusion-burden patients with lower-risk myelodysplastic syndromes in a phase ii study. J. Clin. Oncol. 39, 48–56 (2021). This paper reports clinical responses of imetelstat in high transfusion-burden patients with MDS.
Herbert, B. S. et al. Lipid modification of GRN163, an N3'->P5' thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibition. Oncogene. 24, 5262–5268 (2005). This paper describes the structure of imetelstat.
Waksal, J. A. et al. Telomerase-targeted therapies in myeloid malignancies. Blood Adv. https://doi.org/10.1182/bloodadvances.2023009903 (2023). A review that presents an overview of telomerase-targeted therapies in blood cancers.
Jiang, X. et al. Ferroptosis: mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol. 22, 266–282 (2021). A review that highlights mechanisms of ferroptosis in disease.
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This is a summary of: Bruedigam, C. et al. Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as therapeutic strategy for acute myeloid leukemia. Nat. Cancer https://doi.org/10.1038/s43018-023-00653-5 (2023).
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Telomerase inhibitor imetelstat kills AML cells via lipid ROS and ferroptosis. Nat Cancer 5, 12–13 (2024). https://doi.org/10.1038/s43018-023-00654-4
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DOI: https://doi.org/10.1038/s43018-023-00654-4