Eprenetapopt (APR-246, also known as PRIMA-1MET) can strengthen the anti-tumor activity of venetoclax in acute myeloid leukemia (AML) cells carrying a TP53 mutation, according to a peer-reviewed, accepted study published in the journal Amino Acids on 30 August 2026. The work is an in vitro investigation using cell lines, not a clinical trial, and its findings are limited to laboratory models.
The study set out to test whether APR-246 could enhance the effects of venetoclax (VEN) on cell proliferation and apoptosis in TP53-mutated AML cells, and to explore the mechanisms behind any enhanced effect. Both drugs were tested alone and in combination in TP53 R248Q-mutated AML cell lines.
Cell proliferation was measured with the CCK-8 assay, while apoptosis was evaluated using Western blot analysis and flow cytometry. The researchers report that both APR-246 and venetoclax as single agents showed significant anti-proliferative and pro-apoptotic effects in the TP53 R248Q-mutated AML cell lines. Notably, APR-246 enhanced the therapeutic efficacy of venetoclax in these cells.
To identify the pathways and genes involved, the team used several bioinformatics tools: the Cancer Dependency Map (DepMap), The Cancer Genome Atlas (TCGA) database, gene set enrichment analysis (GSEA), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. These computational approaches helped point toward candidate mechanisms, which the authors emphasize warrant further investigation.
From a mechanistic perspective, the study proposes that APR-246 may exert its anti-leukemic effects through two pathways. The first is associated with downregulation of PPP1CA expression, which could potentially involve the Hippo signaling pathway, coinciding with the observed inhibition of proliferation and induction of apoptosis.
The second proposed mechanism involves attenuation of venetoclax-induced MCL-1 (myeloid cell leukemia-1) overexpression. The authors suggest that suppressing this overexpression may contribute to the augmented anti-tumor activity seen when APR-246 is combined with venetoclax in the TP53-mutated AML models.
In summary, the authors conclude that in TP53 R248Q-mutated AML cell lines, APR-246 augmented the anti-tumor effects of venetoclax through proliferation inhibition and apoptosis induction. They attribute these enhanced effects to multiple factors, including PPP1CA inhibition, effects on the Hippo pathway, and suppression of MCL-1 expression, while explicitly noting that these mechanisms require further investigation.
However, the present findings come from cell-line experiments only. The abstract does not report results from primary patient samples, animal models, or clinical trials, and the authors describe the mechanistic links as potential rather than established. The article is published as an open-access original article, shared early to provide faster access to peer-reviewed, accepted research; this version is subject to further edits and will be replaced by the final Version of Record.
Subject of Research: In vitro study of APR-246 combined with venetoclax in TP53-mutated AML cell lines
Article Title: APR-246 downregulated PPP1CA to enhance anti-tumor effects of venetoclax in TP53-mutated AML cells
Article References: Liu, H., Li, Z., Tao, S., Shi, Y., Ma, J., Ji, T., Chen, Y., Su, Y., Wang, C., & Yu, L. (2026). APR-246 downregulated PPP1CA to enhance anti-tumor effects of venetoclax in TP53-mutated AML cells. Amino Acids. https://doi.org/10.1007/s00726-026-03553-x
Image Credits: AI Generated
DOI: 10.1007/s00726-026-03553-x
Keywords: APR-246, eprenetapopt, venetoclax, AML, TP53 mutation, PPP1CA, MCL-1, Hippo signaling, apoptosis, acute myeloid leukemia, in vitro study, downregulated
News Source: Nathaniel Bowman. (October 29, 2026). APR-246 boosts venetoclax activity against TP53-mutated AML cells in vitro. Scienmag.
