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

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.

Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction

“…Here, we show that priming tumors with SG restriction improves the efficacy of eprenetapopt in esophageal cancer models. A very recent study also demonstrated synergy between eprenetapopt and asparaginase (an enzyme that degrades asparagine) in acute lymphoblastic leukemia cell lines ( 44 ), which could hint that GSH depletion by eprenetapopt more generally increases cancer cell dependency on exogenous amino acid uptake. Furthermore, the combination of venetoclax (inhibitor of the anti-apoptopic protein BCL-2) and azacitidine has been shown to target mitochondrial metabolism through inhibition of the glutathionylation of complex II of the electron transport chain ( 45 ) and diminishes the uptake of global amino acids in primary patient AML stem cells ( 46 ).…”

Targeting Mutant p53 for Cancer Treatment: Moving Closer to Clinical Use?

“…Reactivation of mutant protein to its wild-type configuration might therefore be expected to also confer sensitivity to these treatments. Supporting evidence for this possibility are the multiple reports showing that compounds that reactivate mutant p53 enhance response to several different clinically used therapeutics [ 18 , 19 , 20 , 21 , 22 ]. Another mechanism by which mutant p53 may confer drug resistance is by inducing expression of the drug efflux pump MDR1 (ABCB1), which promotes efflux of drugs out of tumor cells [ 23 ].…”

Targeting Nutrient Dependency in Cancer Treatment

“…Thus, it prompts a logical theory of combined treatment with ASNase, which depletes asparagine in the extracellular context, and DNA demethylase or histone acetyltransferase inhibitors, which bring down the expression level of ASNS inside cells, and ideally this should be more relevant to ASNase-resistant ALLs, yet to be demonstrated in the future study. An encouraging study shows that compound APR-246 which directly targets ASNS induces synergistic growth suppression when combined with ASNase treatment in ALL cells (32). Like all other chemical drugs, ASNase is not absolutely specific and able to degrade glutamine due to its partial glutaminase activity, which causes cytotoxicity and side-effects during treatment (33,34).…”