Mutant p53-reactivating compound APR-246 synergizes with asparaginase in inducing growth suppression in acute lymphoblastic leukemia cells

Mutant p53-reactivating compound APR-246 synergizes with asparaginase in inducing growth suppression in acute lymphoblastic leukemia cells

Cell Death & Disease

10.1038/s41419-021-03988-y

https://doi.org/10.1038/s41419-021-03988-y

Sophia Ceder, Sofi E. Eriksson, Ying Yu Liang, Emarndeena H. Cheteh, Si Min Zhang, Kenji M. Fujihara, Julie Bianchi, Vladimir J. N. Bykov, Lars Abrahmsen, Nicholas J. Clemons, Pär Nordlund, Sean G. Rudd, Klas G. Wiman

15 July 2021

Ceder, S., Eriksson, S. E., Liang, Y. Y., Cheteh, E. H., Zhang, S. M., Fujihara, K. M., Bianchi, J., Bykov, V. J. N., Abrahmsen, L., Clemons, N. J., Nordlund, P., Rudd, S. G., & Wiman, K. G. (2021). Mutant p53-reactivating compound APR-246 synergizes with asparaginase in inducing growth suppression in acute lymphoblastic leukemia cells. Cell Death & Disease, 12(7). https://doi.org/10.1038/s41419-021-03988-y

Asparaginase depletes extracellular asparagine in the blood and is an important treatment for acute lymphoblastic leukemia (ALL) due to asparagine auxotrophy of ALL blasts. Unfortunately, resistance occurs and has been linked to expression of the enzyme asparagine synthetase (ASNS), which generates asparagine from intracellular sources. Although TP53 is the most frequently mutated gene in cancer overall, TP53 mutations are rare in ALL. However, TP53 mutation is associated with poor therapy response and occurs at higher frequency in relapsed ALL. The mutant p53-reactivating compound APR-246 (Eprenetapopt/PRIMA-1Met) is currently being tested in phase II and III clinical trials in several hematological malignancies with mutant TP53. Here we present CEllular Thermal Shift Assay (CETSA) data indicating that ASNS is a direct or indirect target of APR-246 via the active product methylene quinuclidinone (MQ). Furthermore, combination treatment with asparaginase and APR-246 resulted in synergistic growth suppression in ALL cell lines. Our results thus suggest a potential novel treatment strategy for ALL.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the Swedish Research Council - NA
Grant Reference no. : 2017-01509, 2018-02114

This research / project is supported by the Swedish Cancer Society - NA
Grant Reference no. : 18 0774, 19-0056-JIA, 20-0879-Pj

This research / project is supported by the Swedish Childhood Cancer Fund - NA
Grant Reference no. : PR2017-0106, PR2019- 0014

This research / project is supported by the Radiumhemmets Forskningsfonder - NA
Grant Reference no. : 171213

This research / project is supported by the Knut and Alice Wallenberg Foundation - NA
Grant Reference no. : NA

This research / project is supported by the Robert Lundberg Memorial Foundation - NA
Grant Reference no. : NA

https://oar.a-star.edu.sg/communities-collections/articles/21514

2041-4889

Institute of Molecular and Cell Biology