Lindell Emma, Guo Jing, Zhao Miao, Rameika Natallia, Lu Xi, Wacker Tabea, Zhong Lei, Bergström Tobias, Svanberg Sara, Chowdhury Azazul I, Bergsten Peter, Chen Xingqi, Bexell Daniel, Swartling Fredrik J, Sjöblom Tobias, Zhang Xiaonan
Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85, Uppsala, Sweden.
Centre for Computational Biology, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.
Cell Death Dis. 2025 Jul 23;16(1):554. doi: 10.1038/s41419-025-07876-7.
Amplification of the MYCN proto-oncogene serves as a key marker of aggressive disease and poor treatment outcomes in certain pediatric tumors originating from the nervous system, including neuroblastoma and medulloblastoma. However, the complex nature of the challenging MYCN protein underscores the urgent need for additional targets and therapies to tackle neuroblastoma and medulloblastoma. In this study, with a primary focus on neuroblastoma and the aim of also benefiting children with medulloblastoma, we identified FLIX5, a small compound that exhibits broad cytotoxicity against both neuroblastoma and medulloblastoma cells, primarily by triggering apoptosis. Furthermore, FLIX5 enhances the cholesterol dependency of neuroblastoma cells under conditions where mitochondrial function is impaired. FLIX5 as well shows a synergistic effect when combined with vincristine, a conventional anticancer drug, against neuroblastoma cells and organoids. Through proteome integral solubility alteration, computational molecular docking predictions, and cellular thermal shift assays for target identification and validation, FLIX5 reveals EPLIN (Epithelial Protein Lost In Neoplasm) as a previously unexplored drug target. EPLIN is involved in several cellular processes, including cholesterol uptake and mitochondrial function. The discovery of FLIX5 targeting EPLIN presents new opportunities for treating malignant pediatric tumors, with the potential to target chemoresistant dormant cancer cells and broaden its therapeutic applications to other tumor types.
MYCN原癌基因的扩增是某些起源于神经系统的儿童肿瘤（包括神经母细胞瘤和髓母细胞瘤）侵袭性疾病和治疗效果不佳的关键标志物。然而，具有挑战性的MYCN蛋白的复杂性质凸显了迫切需要额外的靶点和疗法来应对神经母细胞瘤和髓母细胞瘤。在本研究中，我们主要聚焦于神经母细胞瘤，同时旨在使髓母细胞瘤患儿也受益，我们鉴定出了FLIX5，这是一种小分子化合物，主要通过触发凋亡对神经母细胞瘤和髓母细胞瘤细胞均表现出广泛的细胞毒性。此外，在线粒体功能受损的条件下，FLIX5增强了神经母细胞瘤细胞对胆固醇的依赖性。当与传统抗癌药物长春新碱联合使用时，FLIX5对神经母细胞瘤细胞和类器官也显示出协同作用。通过蛋白质组整体溶解度改变、计算分子对接预测以及用于靶点鉴定和验证的细胞热位移分析，FLIX5揭示EPLIN（肿瘤中缺失的上皮蛋白）是一个此前未被探索的药物靶点。EPLIN参与多种细胞过程，包括胆固醇摄取和线粒体功能。靶向EPLIN的FLIX5的发现为治疗儿童恶性肿瘤带来了新机遇，有可能靶向化疗耐药的休眠癌细胞，并将其治疗应用扩展到其他肿瘤类型。
