Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia Journal Article
| Authors: | Bruedigam, C.; Porter, A. H.; Song, A.; Vroeg in de Wei, G.; Stoll, T.; Straube, J.; Cooper, L.; Cheng, G.; Kahl, V. F. S.; Sobinoff, A. P.; Ling, V. Y.; Jebaraj, B. M. C.; Janardhanan, Y.; Haldar, R.; Bray, L. J.; Bullinger, L.; Heidel, F. H.; Kennedy, G. A.; Hill, M. M.; Pickett, H. A.; Abdel-Wahab, O.; Hartel, G.; Lane, S. W. |
| Article Title: | Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia |
| Abstract: | Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft resource and perform integrated genomics, transcriptomics and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized phase II-like preclinical trial in patient-derived xenografts, imetelstat effectively diminishes AML burden and preferentially targets subgroups containing mutant NRAS and oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing substantial disease control in AML. © 2023, The Author(s). |
| Keywords: | controlled study; unclassified drug; gene mutation; human cell; sequence analysis; genetics; leukemia, myeloid, acute; clinical trial; doxorubicin; nonhuman; cancer patient; cytarabine; flow cytometry; multiple reaction monitoring; mouse; phenotype; metabolism; dna damage; cell survival; apoptosis; phase 2 clinical trial; gene expression; confocal microscopy; randomized controlled trial; thrombocytopenia; animal experiment; animal model; cohort analysis; genotype; cytogenetics; tumor xenograft; transcriptomics; telomerase; mononuclear cell; xenograft; splenomegaly; western blotting; immunoblotting; reactive oxygen metabolite; genomics; fatty acids; oxidative stress; leukocyte count; anthracycline; bioinformatics; oligonucleotide; fluorescence activated cell sorting; fatty acid; lipid peroxidation; lipid metabolism; deferoxamine; rna sequence; oligonucleotides; hematocrit; linoleic acid; sulfamethoxazole; trimethoprim; streptococcus pyogenes; acute myeloid leukemia; gene ontology; fatty acid metabolism; palmitic acid; polyunsaturated fatty acid; telomere length; mapk signaling; ferroptosis; physiological stress; lipidomics; sanger sequencing; humans; human; male; female; article; ultra performance liquid chromatography; ic50; venetoclax; whole exome sequencing; crenolanib; gilteritinib; gene editing; crispr-cas9 system; cell proliferation assay; imetelstat; liproxstatin |
| Journal Title: | Nature Cancer |
| Volume: | 5 |
| Issue: | 1 |
| ISSN: | 2662-1347 |
| Publisher: | Nature Research |
| Date Published: | 2024-01-01 |
| Start Page: | 47 |
| End Page: | 65 |
| Language: | English |
| DOI: | 10.1038/s43018-023-00653-5 |
| PUBMED: | 37904045 |
| PROVIDER: | scopus |
| PMCID: | PMC10824665 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
