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More effective therapies are especially important for these patients. CUDC-907, a novel dual inhibitor targeting the MYC upstream pathway (HDAC\/PI3K), shows significant antitumor efficacy across multiple cancer types. However, the antitumor effects and underlying mechanisms of CUDC-907 in MB, particularly in very high-risk MB, remain unexplored. In this study, we showed that MYC amplified G3 MB cells, patient-derived organoids and xenograft models were sensitive to CUDC-907. CUDC\u2010907 inhibited MYC expression through the HDAC and PI3K pathways, and then induced G0\/G1 phase arrest through the MYC-P21\/P27-CDKs\/cyclins axis. Furthermore, when CUDC-907 was combined with chemotherapeutic drug cisplatin, G0\/G1 phase blocking effect was further enhanced. CUDC-907 in combination with radiotherapy (RT) inhibited DNA damage repair and increased DNA damage. These findings indicate that CUDC-907, either as a monotherapy or in combination with chemoradiotherapy, represents a promising therapeutic strategy for MYC amplified G3 MB, potentially influencing future clinical trials targeting this patient population.<\/jats:p>","DOI":"10.1038\/s41420-025-02470-4","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T11:08:57Z","timestamp":1744628937000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The dual HDAC\/PI3K inhibitor CUDC-907 inhibits the growth and proliferation of MYC-driven Group 3 medulloblastoma"],"prefix":"10.1038","volume":"11","author":[{"given":"Pan","family":"Gou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chencheng","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanxuan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Gan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjin","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1178-1570","authenticated-orcid":false,"given":"Hongjuan","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7409-9504","authenticated-orcid":false,"given":"Ping","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,14]]},"reference":[{"key":"2470_CR1","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1007\/s00401-016-1545-1","volume":"131","author":"NL David","year":"2016","unstructured":"David NL, Arie P, Guido R, Andreas VD, Dominique F-B, Webster KC, et al. 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