Mutant p53-reactivating compound APR-246 synergizes with asparaginase in inducing growth suppression in acute lymphoblastic leukemia cells.
Cell Death Dis
; 12(7): 709, 2021 07 15.
Article
em En
| MEDLINE
| ID: mdl-34267184
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Asparaginase
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Quinuclidinas
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Protocolos de Quimioterapia Combinada Antineoplásica
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Proteína Supressora de Tumor p53
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Proliferação de Células
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Leucemia-Linfoma Linfoblástico de Células Precursoras
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Mutação
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article