| Autor: |
Ebner, Jessica, Schmoellerl, Johannes, Piontek, Martin, Manhart, Gabriele, Troester, Selina, Carter, Bing Z., Neubauer, Heidi, Moriggl, Richard, Szakács, Gergely, Zuber, Johannes, Köcher, Thomas, Andreeff, Michael, Sperr, Wolfgang R., Valent, Peter, Grebien, Florian |
| Předmět: |
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| Zdroj: |
Nature Communications; 9/19/2023, Vol. 14 Issue 1, p1-16, 16p |
| Abstrakt: |
The BCL-2 inhibitor Venetoclax is a promising agent for the treatment of acute myeloid leukemia (AML). However, many patients are refractory to Venetoclax, and resistance develops quickly. ATP-binding cassette (ABC) transporters mediate chemotherapy resistance but their role in modulating the activity of targeted small-molecule inhibitors is unclear. Using CRISPR/Cas9 screening, we find that loss of ABCC1 strongly increases the sensitivity of AML cells to Venetoclax. Genetic and pharmacologic ABCC1 inactivation potentiates the anti-leukemic effects of BCL-2 inhibitors and efficiently re-sensitizes Venetoclax-resistant leukemia cells. Conversely, ABCC1 overexpression induces resistance to BCL-2 inhibitors by reducing intracellular drug levels, and high ABCC1 levels predicts poor response to Venetoclax therapy in patients. Consistent with ABCC1-specific export of glutathionylated substrates, inhibition of glutathione metabolism increases the potency of BCL-2 inhibitors. These results identify ABCC1 and glutathione metabolism as mechanisms limiting efficacy of BCL-2 inhibitors, which may pave the way to development of more effective therapies. BCL-2 inhibition using Venetoclax has emerged as a promising therapy in Acute Myeloid Leukaemia (AML), but primary and acquired resistance is a main limitation of this treatment. Here, the authors show that the ABC transporter ABCC1 (MRP1) together with glutathione, are associated with Venetoclax resistance and represent potential targets to sensitize AML cells to BCL-2 inhibition. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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