Guo Chen, Long Zhilin, Lin Peng, Shen Yinan, Zhong Yiye, Qian Jingjing, Yu Jichuan, Zhao Weixi, Liu Fuyi, Ma Yiling, Zheng Jian, Yang Jiayao, Zhao Shuai, Ran Xiaojuan, Xia Zhen, Wu Congying, Cai Yujia, Wang Chen, Xie Qi
College of Life Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Growth Regulation and Transformation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310030, China; Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310030, China; School of Life Sciences, Westlake University, Hangzhou 310030, China.
Key Laboratory of Growth Regulation and Transformation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310030, China; Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310030, China; School of Life Sciences, Westlake University, Hangzhou 310030, China.
Cell Rep Med. 2025 Aug 19;6(8):102258. doi: 10.1016/j.xcrm.2025.102258. Epub 2025 Jul 30.
Long-term survival of glioblastoma multiforme (GBM) remains challenging, spurring the development of novel therapies such as oncolytic virus therapy. While oncolytic virus shows promise in clinical trials, many patients do not respond to this therapy. Here, we perform a CRISPR screening and identify the non-canonical BRG1/BRM-associated factor (ncBAF) complex as a pivotal tumor-intrinsic factor for oncolytic virotherapy resistance. Knocking out the ncBAF-specific subunit bromodomain-containing protein 9 (BRD9) markedly augments the oncolytic efficacy of oncolytic herpes simplex virus type 1 (oHSV1) and enhances antitumor immunity. Mechanistically, BRD9 binds to RELA and potentiates the expression of downstream antiviral genes. Notably, the application of BRD9 inhibitor (IBRD9) significantly enhances the oncolytic activity of oHSV1 in various GBM models. Moreover, reduced BRD9 levels strongly correlate with improved outcomes in clinical trials of oHSV1. These findings suggest that BRD9 is an attractive target for overcoming the resistance to oHSV1 in glioblastoma treatment.
多形性胶质母细胞瘤（GBM）的长期生存仍然具有挑战性，这推动了诸如溶瘤病毒疗法等新型疗法的发展。虽然溶瘤病毒在临床试验中显示出前景，但许多患者对这种疗法没有反应。在这里，我们进行了一项CRISPR筛选，并确定非经典BRG1/BRM相关因子（ncBAF）复合物是溶瘤病毒疗法耐药性的关键肿瘤内在因素。敲除ncBAF特异性亚基含溴结构域蛋白9（BRD9）可显著增强1型溶瘤单纯疱疹病毒（oHSV1）的溶瘤效力，并增强抗肿瘤免疫力。从机制上讲，BRD9与RELA结合并增强下游抗病毒基因的表达。值得注意的是，BRD9抑制剂（IBRD9）的应用在各种GBM模型中显著增强了oHSV1的溶瘤活性。此外，在oHSV1的临床试验中，BRD9水平降低与更好的结果密切相关。这些发现表明，BRD9是克服胶质母细胞瘤治疗中对oHSV1耐药性的一个有吸引力的靶点。
