Mutant p53-reactivating compound APR-246 synergizes with asparaginase in inducing growth suppression in acute lymphoblastic leukemia cells
Year: 2021
Type: article
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.
Source: Cell Death and Disease
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,170
Awards: G1147202773, G1896045634, Reaktivering av tumörsuppressorgenerna TP53, RB1 och PTEN i barntumörer, Further studies of the p53 tumor suppressor pathway and development of novel efficient cancer therapy, Med SAMHD1 enzymet i sikte kunna förbättra behandlingen av hematologiska maligniteter hos barn, Targeting SAMHD1 to enhance existing cancer therapies, G6138180563, G712881263, G7520224199
OpenAlex ID: W3178806744