19.09.2023: One focus of research at the University of Veterinary Medicine Vienna is on leukaemia and the identification of novel treatment options. An international group of researchers led by Vetmeduni is now delivering important findings on Venetoclax, a medication that was approved in 2021 to treat newly diagnosed acute myeloid leukaemia (AML) in adults. Many patients do not respond to Venetoclax, however, and quickly develop resistance. A recently published study in Nature Communications shows how this can be counteracted.
Venetoclax is a BCL-2 inhibitor and a promising treatment for acute myeloid leukaemia (AML). Many patients do not respond to Venetoclax, however, and quickly develop resistance. ATP-binding cassette transporters (ABC transporters) – membrane transport proteins (carriers) that transport molecules out of the cell – mediate resistance to chemotherapeutic drugs, but their role in the context of BCL-2 inhibitors has been unclear so far.
ABCC1 and glutathione metabolism limit efficacy of Venetoclax
Using CRISPR/Cas9 screening, the researchers found that the ABC transporter protein ABCC1 plays a role in limiting the efficacy of Venetoclax in cancer cells. Several previous studies had already identified ABCC1 as a resistance factor against a number of other drugs. The researchers further discovered that glutathione metabolism also affects the efficacy of Venetoclax. Glutathione is a tripeptide protein and one of the most important antioxidants in the human body, found in high concentrations in almost all cells.
As Jessica Ebner from the Institute for Medical Biochemistry at Vetmeduni explains: “Loss of ABCC1 strongly increases the sensitivity of AML cells to Venetoclax. Genetic and pharmacologic ABCC1 inactivation potentiates the anti-leukaemic effects of BCL-2 inhibitors and efficiently re-sensitizes Venetoclax-resistant leukaemia.”
“Conversely, ABCC1 overexpression induces resistance to BCL-2 inhibitors by reducing intracellular drug levels, and a high ABCC1 level predicts poor response to Venetoclax therapy in patients. Inhibition of glutathione metabolism, meanwhile, increases the potency of BCL-2 inhibitors,” says Johannes Schmoellerl from the Research Institute of Molecular Pathology (IMP) in Vienna.
Strategies for overcoming Venetoclax resistance
The study identifies ABCC1 and glutathione metabolism as mechanisms limiting efficacy of BCL-2 inhibitors, which may pave the way for the development of more effective therapies: “Our study proposes ABCC1 as a functional biomarker for the response of AML cells to inhibitors from the BCL-2-family. The results further suggest that interfering with ABCC1 function or glutathione metabolism are rational strategies for overcoming Venetoclax resistance,” says Florian Grebien, Head of the Institute for Medical Biochemistry at Vetmeduni and since spring 2023 principal investigator at the St. Anna Children’s Cancer Research Institute. According to Grebien, the data highlight that membrane transporters could serve as promising intervention points to enhance the effectiveness of small molecular inhibitors in leukaemia and beyond.
The article “ABCC1 and glutathione metabolism limit the efficacy of BCL-2 inhibitors in acute myeloid leukemia” by 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 was published in Nature Communications.