非典型畸胎瘤样横纹肌样瘤 (ATRT) 是一种罕见、破坏性且基本上无法治愈的儿童脑肿瘤。尽管最近的研究发现了 ATRT 的三个分子亚组，它们具有不同的疾病模式和信号传导特征，但 ATRT 亚组的治疗概况仍未完全阐明。我们检查了 465 种激酶抑制剂对一组 ATRT 亚组特异性细胞系的影响。然后，我们应用多组学分析来研究 ATRT 亚组中激酶抑制剂功效的潜在分子机制。我们观察到 ATRT 细胞系对 PI3K 和 MAPK 信号通路以及 CDK、AURKA/B 激酶、和 PLK1。我们在 MYC/TYR ATRT 细胞中确定了两类主要针对受体酪氨酸激酶 (RTK) 的多激酶抑制剂 (MKI)，包括 PDGFR 和 EGFR/ERBB2。 PDGFRB 抑制剂 Dasatinib 与广泛作用的 PI3K 和 MAPK 通路抑制剂（包括 Rapamycin 和 Trametinib）联合使用时，可协同影响 MYC/TYR ATRT 细胞的生长。我们观察到 MYC/TYR ATRT 细胞对 ERBB2 信号传导的各种抑制剂也明显敏感。原代 MYC/TYR ATRT 的转录、H3K27Ac ChIPSeq、ATACSeq 和 HiChIP 分析揭示了 ERBB2 表达，其与差异甲基化和通过 DNA 环激活不同增强子元件相关。值得注意的是，我们发现脑渗透性 EGFR/ERBB2 抑制剂阿法替尼在体外和体内特异性抑制 MYC/TYR ATRT 细胞的生长。综上所述，我们的研究表明将 PDGFR 和 ERBB2 导向的 TKI 与 PI3K 和 MAPK 抑制剂联合治疗途径作为 ATRT 的 MYC/TYR 亚组的重要新治疗策略。© 作者 2024。由牛津大学出版社代表神经肿瘤学会出版。版权所有。如需商业重复使用，请联系 reprints@oup.com 获取转载和转载的翻译权。所有其他权限都可以通过我们网站文章页面上的权限链接通过我们的 RightsLink 服务获得 - 如需了解更多信息，请联系journals.permissions@oup.com。

Atypical Teratoid Rhabdoid Tumor (ATRT) is a rare, devastating, and largely incurable pediatric brain tumor. Although recent studies have uncovered three molecular subgroups of ATRTs with distinct disease patterns, and signaling features, the therapeutic profiles of ATRT subgroups remain incompletely elucidated.We examined the effect of 465 kinase inhibitors on a panel of ATRT subgroup-specific cell lines. We then applied multi-omics analyses to investigate the underlying molecular mechanism of kinase inhibitor efficacy in ATRT subgroups.We observed that ATRT cell lines are broadly sensitive to inhibitors of the PI3K and MAPK signaling pathways, as well as CDKs, AURKA/B kinases, and PLK1. We identified two classes of multi-kinase inhibitors (MKIs) predominantly targeting receptors tyrosine kinase (RTKs) including PDGFR and EGFR/ERBB2 in MYC/TYR ATRT cells. The PDGFRB inhibitor, Dasatinib, synergistically affected MYC/TYR ATRT cell growth when combined with broad-acting PI3K and MAPK pathway inhibitors, including Rapamycin and Trametinib. We observed that MYC/TYR ATRT cells were also distinctly sensitive to various inhibitors of ERBB2 signaling. Transcriptional, H3K27Ac ChIPSeq, ATACSeq, and HiChIP analyses of primary MYC/TYR ATRTs revealed ERBB2 expression which correlated with differential methylation and activation of a distinct enhancer element by DNA looping. Significantly, we show the brain penetrant EGFR/ERBB2 inhibitor, Afatinib, specifically inhibited in vitro and in vivo growth of MYC/TYR ATRT cells.Taken together our studies suggest combined treatments with PDGFR and ERBB2-directed TKIs with inhibitors of the PI3K and MAPK pathways as an important new therapeutic strategy for the MYC/TYR subgroup of ATRTs.© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.