{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T11:05:24Z","timestamp":1784199924002,"version":"3.55.0"},"reference-count":53,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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\u2010enhancer addiction. The transcriptional co\u2010activator p300 acts as a critical \u201cwriter\u201d 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Assay for Transposase\u2010Accessible Chromatin with high\u2010throughput sequencing (ATAC\u2010seq) 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\u2010generation XPO1 inhibitor KPT8602 (Eltanexor) using proliferation assays, cell cycle analysis, and Chou\u2010Talalay synergy modeling in\u00a0vitro and in\u00a0vivo. Finally, RNA sequencing was employed to elucidate the molecular mechanisms underlying MM cell sensitivity to A485 treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MM cells exhibited a globally increased chromatin accessibility profile enriched for B\u2010cell 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\u2010ISS stage. A485 treatment or p300 knockdown significantly reduced H3K27ac levels, leading to the downregulation of super\u2010enhancer\u2010associated oncogenes (e.g.,\n                      <jats:italic>MYC<\/jats:italic>\n                      ,\n                      <jats:italic>IRF4<\/jats:italic>\n                      ) and cell cycle arrest. Importantly, A485 synergized with KPT8602 (CI\u2009&lt;\u20091) by dual\u2010targeting the transcriptional generation (p300\u2010mediated) and nuclear export (XPO1\u2010mediated) of oncogenic factors. This combination achieved superior tumor suppression in\u00a0vivo compared to monotherapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.71985","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T03:57:07Z","timestamp":1780459027000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synergistic Antitumor Activity of HAT Inhibitor A485 and XPO1 Inhibitor KPT8602 in Multiple Myeloma"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3255-5177","authenticated-orcid":false,"given":"Hong","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Tianjin First Central Hospital, School of Medicine Nankai University  Tianjin China"},{"name":"Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical 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