A485 Targets EP300 in Lymphoma, Boosted by XPO1 Inhibition

In the relentless quest to uncover new therapeutic avenues for diffuse large B-cell lymphoma (DLBCL), a recent study published in BMC Cancer sheds illuminating light on the potential of targeting the epigenetic regulator EP300. This aggressive hematological malignancy, known for its rapid progression and clinical complexity, demands innovative treatment strategies. Researchers have now identified EP300, a pivotal lysine acetyltransferase, as a promising target, unveiling the potent antitumor effects of the small-molecule inhibitor A485, especially when combined synergistically with XPO1 inhibition.

DLBCL represents the most common subtype of non-Hodgkin lymphoma, characterized by the uncontrolled proliferation of large B cells. Despite advances in chemotherapy and immunotherapy, relapse and resistance remain significant clinical hurdles. In this context, epigenetic dysregulation, including aberrant histone modifications, has come under intense scrutiny for its role in oncogenesis. The enzyme EP300, part of the KAT3 family, exerts profound influence on gene expression through acetylation of histone H3 at lysine 27 (H3K27Ac), thereby regulating chromatin accessibility and transcriptional activation.

Until now, the precise contribution of EP300 to DLBCL pathogenesis was poorly understood. This knowledge gap was addressed by collecting and analyzing extensive public datasets, which revealed that EP300 is frequently overexpressed in DLBCL tumor samples. Importantly, high EP300 expression correlated strongly with adverse clinical outcomes, suggesting its involvement in driving lymphoma progression. These associations underscored the therapeutic potential of EP300 inhibition to disrupt malignant transcriptional programs.

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The research team employed A485, a newly developed, selective inhibitor targeting the histone acetyltransferase (HAT) domain of EP300, to probe its antineoplastic potential. In vitro experiments demonstrated that treatment with A485 substantially reduced H3K27 acetylation levels in DLBCL cells, effectively damping the aberrant epigenetic activation that fuels tumor growth. This molecular disruption translated into pronounced cytotoxicity, with marked decreases in cell proliferation and colony formation capacity.

Beyond cellular assays, the efficacy of A485 was rigorously tested in animal models bearing DLBCL xenografts. Remarkably, A485 treatment yielded significant tumor suppression without causing overt toxicity, underscoring its therapeutic index. Mechanistic studies revealed that A485 interfered with critical oncogenic signaling cascades, notably by downregulating the MYC and E2F1 transcriptional pathways, which are well-established drivers of cell cycle progression and survival in lymphoma cells.

While A485 alone demonstrated encouraging antitumor activity, the study ventured further by combining EP300 inhibition with blockade of nuclear export via the XPO1 inhibitor KPT8602. XPO1 is responsible for the translocation of numerous tumor suppressors and growth regulators from the nucleus to the cytoplasm; its inhibition has emerged as a promising target in hematological malignancies. The combinatorial approach unleashed a potent synergistic effect, amplifying apoptosis induction and growth arrest in DLBCL cell lines far beyond the effects of either agent alone.

In vivo experiments mirrored this synergy: mice subjected to the dual treatment regimen experienced enhanced tumor regression compared to single-agent therapies, without exacerbation of toxicity markers. This finding suggests a compelling therapeutic window for co-targeting EP300-mediated epigenetic modifications and nuclear export processes. Such combination strategies hold promise to overcome treatment resistance and improve long-term outcomes for patients with refractory DLBCL.

The molecular underpinnings of this synergism were probed through RNA sequencing analyses, which unveiled a coordinated suppression of oncogenic transcriptional networks and disruption of cell cycle checkpoints. By dampening the epigenetic support for MYC and E2F1 activity while simultaneously hampering nuclear export of key regulatory proteins, the combination treatment orchestrates a multipronged assault on lymphoma cell survival mechanisms.

Clinically, these insights could usher in a new paradigm of targeted therapy for DLBCL, shifting focus toward epigenetic enzymes like EP300 as druggable vulnerabilities. The specificity of A485 for the HAT domain permits selective modulation of pathological acetylation without broadly compromising essential cellular functions. Furthermore, the capacity to amplify therapeutic efficacy through rational combination with XPO1 inhibitors opens avenues for tailored regimens that maximize tumor kill and minimize systemic toxicity.

This study also highlights the expanding horizon of precision oncology, where integrative analyses of genetic, epigenetic, and proteomic landscapes inform the development of novel agents. The identification of EP300 overexpression as a biomarker correlating with poor prognosis could aid in stratifying patients who may benefit from such targeted interventions. As research progresses, biomarker-guided clinical trials will be pivotal in translating these preclinical findings into standard-of-care treatments.

Moreover, the research accentuates the importance of epigenetic regulation in hematologic malignancies, an area previously underexplored relative to genomic mutations. Targeting epigenetic modifiers offers a dynamic approach to reverse aberrant transcriptional states driving cancer progression. The success with A485 substantiates the concept that enzymes modulating chromatin architecture represent viable and potent targets in DLBCL as well as potentially other cancers.

The synergy observed with XPO1 inhibition also reflects the intricate crosstalk between epigenetic regulation and nuclear-cytoplasmic transport in maintaining oncogenic programs. Blocking XPO1 function traps tumor suppressors and regulatory factors within the nucleus, where they can reinitiate growth-inhibitory signals. When combined with EP300 inhibition, this nuclear retention likely heightens tumor cell vulnerability, inducing apoptosis and impairing proliferation robustly.

Future research directions will involve elucidating the broader applicability of EP300 and XPO1 co-inhibition across diverse lymphoma subtypes and resistance profiles. Additionally, exploring potential off-target effects and optimizing dosing regimens to enhance therapeutic index will be crucial for advancing these findings into clinical testing. Identification of resistance mechanisms and combinational partners remains a rich area of investigation poised to refine treatment strategies further.

In conclusion, the study presents compelling evidence that targeting the epigenetic regulator EP300 with A485, particularly when combined with the XPO1 inhibitor KPT8602, exerts potent antitumor effects against DLBCL. These findings herald a promising therapeutic avenue rooted in the disruption of aberrant acetylation and nuclear export pathways critical to lymphoma progression. As research advances, such precision-based interventions may significantly improve survival and quality of life for patients afflicted by this challenging malignancy.

Subject of Research: Targeting epigenetic regulation in diffuse large B-cell lymphoma (DLBCL) through EP300 inhibition and its synergy with XPO1 blockade.

Article Title: Targeting EP300 in diffuse large b-cell lymphoma: efficacy of A485 and synergistic effects with XPO1 inhibition

Article References:
Jiang, Y., Xing, D., He, X. et al. Targeting EP300 in diffuse large b-cell lymphoma: efficacy of A485 and synergistic effects with XPO1 inhibition. BMC Cancer 25, 955 (2025). https://doi.org/10.1186/s12885-025-14257-y

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14257-y

Tags: A485 small-molecule inhibitorantitumor effects of EP300 targetingcancer therapy innovation strategiesdiffuse large B-cell lymphoma treatmentDLBCL clinical challengesEP300 epigenetic regulatorgene expression and chromatin accessibilityhistone modification in lymphomalysine acetyltransferase role in cancernon-Hodgkin lymphoma researchoncogenesis and epigenetic dysregulationXPO1 inhibition synergy