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

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

  • Nat Commun. 2023 Sep 19;14(1):5709. doi: 10.1038/s41467-023-41229-2.
Jessica Ebner # 1,  Johannes Schmoellerl # 1 2,  Martin Piontek 1,  Gabriele Manhart 1,  Selina Troester 1,  Bing Z Carter 3,  Heidi Neubauer 4,  Richard Moriggl 4,  Gergely Szakács 5 6,  Johannes Zuber 2 7,  Thomas Köcher 8,  Michael Andreeff 3,  Wolfgang R Sperr 9 10,  Peter Valent 9 10,  Florian Grebien 11 12
Affiliations

Affiliations

  • 1 Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria.
  • 2 Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria.
  • 3 Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Institute for Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
  • 5 Center for Cancer Research, Medical University Vienna, Vienna, Austria.
  • 6 Institute of Enzymology, Research Centre of Natural Sciences, Eötvös Loránd Research Network, Budapest, Hungary.
  • 7 Medical University of Vienna, Vienna, Austria.
  • 8 Vienna BioCenter Core Facilities, Vienna BioCenter, Vienna, Austria.
  • 9 Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
  • 10 Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.
  • 11 Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria. [email protected].
  • 12 St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria. [email protected].
  • # Contributed equally.
PMID: 37726279 DOI: 10.1038/s41467-023-41229-2
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.

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