Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia.
Claudia BruedigamAmy H PorterAxia SongGerjanne Vroeg In de WeiThomas StollJasmin StraubeLeanne CooperGuidan ChengVivian F S KahlAlexander P SobinoffVictoria Y LingBilly Michael Chelliah JebarajYashaswini JanardhananRohit HaldarLaura J BrayLars BullingerFlorian H HeidelGlen A KennedyMichelle M HillHilda A PickettOmar Abdel-WahabGunter F HartelSteven W LanePublished in: Nature cancer (2023)
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.
Keyphrases
- acute myeloid leukemia
- fatty acid
- oxidative stress
- crispr cas
- phase ii
- genome wide
- allogeneic hematopoietic stem cell transplantation
- gene expression
- cell death
- clinical trial
- dna methylation
- genome editing
- dna damage
- single cell
- open label
- diabetic rats
- induced apoptosis
- phase iii
- transcription factor
- acute lymphoblastic leukemia
- squamous cell carcinoma
- stem cells
- case report
- signaling pathway
- locally advanced
- cell therapy
- placebo controlled
- heat stress