Mutant p53-reactivating compound APR-246 synergizes with asparaginase in inducing growth suppression in acute lymphoblastic leukemia cells
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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.
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Eprenetapopt and asparaginase synergize in acute lymphoblastic leukemia cell lines.
“A very recent study also demonstrated synergy between eprenetapopt and asparaginase (an enzyme that degrades asparagine) in acute lymphoblastic leukemia cell lines (44)”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [44]
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Targeting p53 pathways: mechanisms, structures, and advances in therapy
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- Authors
- 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.
- Affiliations
- Karolinska Institutet (SE)
- Agency for Science, Technology and Research (SG)
- Science for Life Laboratory (SE)
- The University of Melbourne (AU)
- Corresponding author
- Wiman, Klas G.
- ORCID
- Venue
- Cell Death & Disease
- Published
- 2021-07-15
- Volume
- 12
- Issue
- 7
- Pages
- 709-709
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC8282662
- OpenAlex
- W3178806744
- Cited by
- 18
- References
- 72
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 9
- FWCI
- 2.81
- Type
- journal article
- Language
- en
- Update notices
- correction (2022-08-03)
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Funders
- Robert Lundbergs Minnesstiftelse
- Vetenskapsrådet (2017-01509)
- Cancerfonden (18 0774)
- Barncancerfonden (PR2017-0106)
- Radiumhemmets Forskningsfonder (171213)
- Knut och Alice Wallenbergs Stiftelse
- Karolinska Institutet
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- APR-246, PRIMA-1MET, L-asparaginase, acute lymphoblastic leukemia, asparagine synthetase, TP53 mutation, mutant p53 reactivation, drug synergy, combination therapy, drug resistance, cellular thermal shift assay
- MeSH terms
- Antineoplastic Combined Chemotherapy Protocols, Asparaginase, Drug Synergism, Humans, Mutation, Quinuclidines, Tumor Suppressor Protein p53, Drug Resistance, Neoplasm, Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor, Cell Line, Tumor, Cell Proliferation, Precursor Cell Lymphoblastic Leukemia-Lymphoma
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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