Synergistic Antitumor Activity of HAT Inhibitor A485 and XPO1 Inhibitor KPT8602 in Multiple Myeloma.

BACKGROUND: Multiple myeloma (MM) remains the second most common hematologic malignancy, necessitating the identification of novel therapeutic targets. MM is characterized by a distinct epigenetic landscape driven by aberrant chromatin activation and super-enhancer addiction. The transcriptional co-activator p300 acts as a critical "writer" of this landscape by depositing H3K27ac marks. In this study, we hypothesized that targeting the histone acetyltransferase (HAT) activity of p300 with the selective inhibitor A485 would collapse this oncogenic chromatin network and induce lethality in MM cells.

METHODS: Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) and public databases (GSE136337, MMRF CoMMpass, Oncomine) were utilized to evaluate MM chromatin accessibility landscapes and to investigate the role of p300 in transcriptional regulation. Gene knockdown, flow cytometry, colony formation assays and western blot analysis were performed to elucidate the functional involvement of p300 in MM cell proliferation. We evaluated the efficacy of A485 alone and in combination with the second-generation XPO1 inhibitor KPT8602 (Eltanexor) using proliferation assays, cell cycle analysis, and Chou-Talalay synergy modeling in vitro and in vivo. Finally, RNA sequencing was employed to elucidate the molecular mechanisms underlying MM cell sensitivity to A485 treatment.

RESULTS: MM cells exhibited a globally increased chromatin accessibility profile enriched for B-cell differentiation and stress response pathways, distinguishing them from normal plasma cells. High p300 expression in newly diagnosed patients correlated with poor overall survival prognosis (OS) and advanced R-ISS stage. A485 treatment or p300 knockdown significantly reduced H3K27ac levels, leading to the downregulation of super-enhancer-associated oncogenes (e.g., MYC, IRF4) and cell cycle arrest. Importantly, A485 synergized with KPT8602 (CI < 1) by dual-targeting the transcriptional generation (p300-mediated) and nuclear export (XPO1-mediated) of oncogenic factors. This combination achieved superior tumor suppression in vivo compared to monotherapy.

CONCLUSION: Our findings position p300 as a central architect of pathogenic chromatin activation in MM. The combination of HAT inhibition (A485) and nuclear export inhibition (KPT8602) represents a novel, mechanistically rationalized therapeutic strategy to overcome epigenetic plasticity in MM.