Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
Neuro Oncol. 2023 Apr 6;25(4):735-747. doi: 10.1093/neuonc/noac199.
Pilocytic astrocytoma (PA) is the most common pediatric brain tumor and a mitogen-activated protein kinase (MAPK)-driven disease. Oncogenic MAPK-signaling drives the majority of cells into oncogene-induced senescence (OIS). While OIS induces resistance to antiproliferative therapies, it represents a potential vulnerability exploitable by senolytic agents.
We established new patient-derived PA cell lines that preserve molecular features of the primary tumors and can be studied in OIS and proliferation depending on expression or repression of the SV40 large T antigen. We determined expression of anti-apoptotic BCL-2 members in these models and primary PA. Dependence of senescent PA cells on anti-apoptotic BCL-2 members was investigated using a comprehensive set of BH3 mimetics.
Senescent PA cells upregulate BCL-XL upon senescence induction and show dependency on BCL-XL for survival. BH3 mimetics with high affinity for BCL-XL (BCL-XLi) reduce metabolic activity and induce mitochondrial apoptosis in senescent PA cells at nano-molar concentrations. In contrast, BH3 mimetics without BCL-XLi activity, conventional chemotherapy, and MEK inhibitors show no effect.
Our data demonstrate that BCL-XL is critical for survival of senescent PA tumor cells and provides proof-of-principle for the use of clinically available BCL-XL-dependent senolytics.
毛细胞星形细胞瘤（PA）是最常见的儿童脑肿瘤，也是一种丝裂原活化蛋白激酶（MAPK）驱动的疾病。致癌的 MAPK 信号驱动大多数细胞进入癌基因诱导的衰老（OIS）。虽然 OIS 会导致对抗增殖治疗产生耐药性，但它代表了一种可以通过衰老细胞选择性溶解剂（senolytic agents）利用的潜在弱点。
我们建立了新的患者来源的 PA 细胞系，这些细胞系保留了原发肿瘤的分子特征，可以在 OIS 和增殖中进行研究，具体取决于 SV40 大 T 抗原的表达或抑制。我们在这些模型和原发性 PA 中确定了抗凋亡 BCL-2 成员的表达。使用一组全面的 BH3 模拟物研究了衰老 PA 细胞对抗凋亡 BCL-2 成员的依赖性。
衰老诱导后，衰老的 PA 细胞上调 BCL-XL，并表现出对 BCL-XL 生存的依赖性。高亲和力结合 BCL-XL 的 BH3 模拟物（BCL-XLi）以纳摩尔浓度在衰老的 PA 细胞中降低代谢活性并诱导线粒体凋亡。相比之下，没有 BCL-XLi 活性的 BH3 模拟物、传统化疗和 MEK 抑制剂则没有效果。
我们的数据表明，BCL-XL 对于衰老的 PA 肿瘤细胞的存活至关重要，并为使用临床可用的依赖 BCL-XL 的衰老细胞选择性溶解剂提供了原理验证。
