ABCC1 and Glutathione Metabolism Limit the Efficacy of Bcl-2 Inhibitors in Acute Myeloid Leukemia

Authors

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
Florian Grebien

Publication Date

9-19-2023

Journal

Nature Communications

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.

Keywords

Humans, Sulfonamides, ATP-Binding Cassette Transporters, Antineoplastic Agents, Leukemia, Myeloid, Acute, Glutathione, Proto-Oncogene Proteins c-bcl-2

Comments

Supplementary Materials

PMID: 37726279