Classic and targeted anti‐leukaemic agents interfere with the cholesterol biogenesis metagene in acute myeloid leukaemia: Therapeutic implications
Open Access
- 25 May 2020
- journal article
- research article
- Published by Wiley in Journal of Cellular and Molecular Medicine
- Vol. 24 (13), 7378-7392
- https://doi.org/10.1111/jcmm.15339
Abstract
Despite significant advances in deciphering the molecular landscape of acute myeloid leukaemia (AML), therapeutic outcomes of this haematological malignancy have only modestly improved over the past decades. Drug resistance and disease recurrence almost invariably occur, highlighting the need for a deeper understanding of these processes. While low O2 compartments, such as bone marrow (BM) niches, are well‐recognized hosts of drug‐resistant leukaemic cells, standard in vitro studies are routinely performed under supra‐physiologic (21% O2, ambient air) conditions, which limits clinical translatability. We hereby identify molecular pathways enriched in AML cells that survive acute challenges with classic or targeted therapeutic agents. Experiments took into account variations in O2 tension encountered by leukaemic cells in clinical settings. Integrated RNA and protein profiles revealed that lipid biosynthesis, and particularly the cholesterol biogenesis branch, is a particularly therapy‐induced vulnerability in AML cells under low O2 states. We also demonstrate that the impact of the cytotoxic agent cytarabine is selectively enhanced by a high‐potency statin. The cholesterol biosynthesis programme is amenable to additional translational opportunities within the expanding AML therapeutic landscape. Our findings support the further investigation of higher‐potency statin (eg rosuvastatin)–based combination therapies to enhance targeting residual AML cells that reside in low O2 environments.Keywords
Funding Information
- National Cancer Institute (1R01CA182905‐01, 1R01CA222007‐01A1, P30 CA082709)
- National Institutes of Health (1S10D012270, UH3TR00943‐01)
- Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii (PN‐III‐P1‐1.1‐MC‐2019‐1167)
- National Institute of Diabetes and Digestive and Kidney Diseases (U54 DK106846)
- Leukemia and Lymphoma Society (8006‐17)
This publication has 55 references indexed in Scilit:
- Sterol regulatory element binding protein-dependent regulation of lipid synthesis supports cell survival and tumor growthCancer & Metabolism, 2013
- Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid LeukemiaNew England Journal of Medicine, 2012
- Differential Effects of Pravastatin and Simvastatin on the Growth of Tumor Cells from Different Organ SitesPLOS ONE, 2011
- Dysregulation of the mevalonate pathway promotes transformationProceedings of the National Academy of Sciences, 2010
- Impact of OATP transporters on pharmacokineticsBritish Journal of Pharmacology, 2009
- Blockade of adaptive defensive changes in cholesterol uptake and synthesis in AML by the addition of pravastatin to idarubicin + high-dose Ara-C: a phase 1 studyBlood, 2006
- Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412Published by American Society of Hematology ,2005
- Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemiaBlood, 2004
- Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy- 3-methylglutaryl coenzyme A reductase inhibitor11CRESTOR is a trademark, the property of AstraZeneca PLC. Research discussed in this article was supported by AstraZeneca.The American Journal of Cardiology, 2001
- Usefulness of nisoldipine for prevention of restenosis after percutaneous transluminal coronary angioplasty (results of the NICOLE study)The American Journal of Cardiology, 2001