Eprenetapopt in combination with Palbociclib exerts synthetic lethality in mantle cell lymphoma

Mantle cell lymphoma (MCL) exhibits distinct biological characteristics and marked molecular heterogeneity, with TP53 mutations associated with particularly poor clinical outcomes. Eprenetapopt (APR-246), a first-in-class mutant p53 reactivator, has shown broad anticancer activity across various tumor types. Palbociclib (PD0332991), a CDK4/6 inhibitor, targets CyclinD1-CDK4/6 complexes to counteract aberrant cell cycle regulation. This project will further explore the anti-tumor efficacy and the potential mechanism of APR-246 combined with PD0332991 in MCL.

In vitro, through assessments of cell proliferation, apoptosis, ROS levels, comet assays, and measurements of DNA damage and apoptosis-related proteins, along with CDX models in vivo, collectively investigated the synergistic anti-tumor efficacy of APR-246 combined with PD0332991 in MCL. Subsequently, through RNA-seq, along with GO functional annotation, KEGG pathway and GSEA enrichment analyses, we were further elucidated the underlying mechanisms and this was confirmed by UHRF1 rescue or knockdown experiments.

In vitro, we found that APR-246 combined with PD0332991 showed synergistic inhibiting cell proliferation, enhancing apoptosis, increasing ROS, and promoted DNA damage in mut/del p53 MCL cells. In vivo, we observed synergistic inhibiting tumor growth without significant toxicity in CDX models. For the mechanism, we further inferred that the APR-246 combined with PD0332991 may coordinate downregulation the expression of UHRF1 and BRCA1 to inhibits the homologous recombination (HR) repair pathway.

These findings support a rational therapeutic strategy that exploits oxidative genomic instability and synthetic lethality via HR pathway disruption, offering a promising combination therapy for managing mut/delp53 MCL.