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

Background: 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. Methods: 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. Results: 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. Conclusion: 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.