Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia.
Dal Bello, Reinaldo
Wu, Hsin Chieh
Castelli, Florence A
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Pardieu, B., Pasanisi, J., Ling, F., Dal Bello, R., Penneroux, J., Su, A., Joudinaud, R., et al. (2022). Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia.. Leukemia https://doi.org/10.1038/s41375-022-01573-6
By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11 impaired the viability and clonogenic capacity of AML cell lines in a cysteine-dependent manner. Sulfasalazine, a broadly available drug with xCT inhibitory activity, had anti-leukemic activity against primary AML samples in ex vivo cultures. Multiple metabolic pathways were impacted upon xCT inhibition, resulting in depletion of glutathione pools in leukemic cells and oxidative stress-dependent cell death, only in part through ferroptosis. Higher expression of cysteine metabolism genes and greater cystine dependency was noted in NPM1-mutated AMLs. Among eight anti-leukemic drugs, the anthracycline daunorubicin was identified as the top synergistic agent in combination with sulfasalazine in vitro. Addition of sulfasalazine at a clinically relevant concentration significantly augmented the anti-leukemic activity of a daunorubicin-cytarabine combination in a panel of 45 primary samples enriched in NPM1-mutated AML. These results were confirmed in vivo in a patient-derived xenograft model. Collectively, our results nominate cystine import as a druggable target in AML and raise the possibility to repurpose sulfasalazine for the treatment of AML, notably in combination with chemotherapy.
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External DOI: https://doi.org/10.1038/s41375-022-01573-6
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336777
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