ABCC1 and glutathione metabolism limit the efficacy of BCL-2 inhibitors in acute myeloid leukemia

Jessica Ebner, Johannes Schmoellerl, Martin Piontek, Gabriele Manhart, Selina Troester, Bing Z. Carter, Heidi Neubauer, Richard Moriggl, Gergely Szakács, Johannes Zuber, Thomas Köcher, Michael Andreeff, Wolfgang R. Sperr, Peter Valent and Florian Grebien ()
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Jessica Ebner: University of Veterinary Medicine Vienna
Johannes Schmoellerl: University of Veterinary Medicine Vienna
Martin Piontek: University of Veterinary Medicine Vienna
Gabriele Manhart: University of Veterinary Medicine Vienna
Selina Troester: University of Veterinary Medicine Vienna
Bing Z. Carter: The University of Texas MD Anderson Cancer Center
Heidi Neubauer: University of Veterinary Medicine Vienna
Richard Moriggl: University of Veterinary Medicine Vienna
Gergely Szakács: Medical University Vienna
Johannes Zuber: Vienna BioCenter (VBC)
Thomas Köcher: Vienna BioCenter
Michael Andreeff: The University of Texas MD Anderson Cancer Center
Wolfgang R. Sperr: Medical University of Vienna
Peter Valent: Medical University of Vienna
Florian Grebien: University of Veterinary Medicine Vienna

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-41229-2

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