Cited by 18Acute Lymphoblastic Leukemia researchCancer-related Molecular PathwaysProtein Tyrosine Phosphatases

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

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Ceder, Sophia, Eriksson, Sofi E., Liang, Ying Yu, Cheteh, Emarndeena H., Zhang, Si Min, Fujihara, Kenji M., Bianchi, Julie, Bykov, Vladimir J. N. +5 more·2021·Cell Death & Disease

Abstract

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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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.
Venue
Cell Death & Disease
Published
2021-07-15
Volume
12
Issue
7
Pages
709-709
ISSN
2041-4889 (ISSN-L)
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
Open access
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

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