Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Berlin Institute of Health, 10178 Berlin, Germany.
Sci Transl Med. 2017 Nov 1;9(414). doi: 10.1126/scitranslmed.aam9078.
Despite intense efforts, the cure rates of childhood and adult solid tumors are not satisfactory. Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined. We have found that the majority of childhood solid tumors, including rhabdoid tumors, neuroblastoma, medulloblastoma, and Ewing sarcoma, express an active DNA transposase, , that can promote site-specific genomic rearrangements in human cells. Using functional genetic approaches, we discovered that mouse and human cells deficient in nonhomologous end joining (NHEJ) DNA repair cannot tolerate the expression of PGBD5. In a chemical screen of DNA damage signaling inhibitors, we identified AZD6738 as a specific sensitizer of PGBD5-dependent DNA damage and apoptosis. We found that expression of PGBD5, but not its nuclease activity-deficient mutant, was sufficient to induce sensitivity to AZD6738. Depletion of endogenous PGBD5 conferred resistance to AZD6738 in human tumor cells. PGBD5-expressing tumor cells accumulated unrepaired DNA damage in response to AZD6738 treatment and underwent apoptosis in both dividing and G-phase cells in the absence of immediate DNA replication stress. Accordingly, AZD6738 exhibited nanomolar potency against most neuroblastoma, medulloblastoma, Ewing sarcoma, and rhabdoid tumor cells tested while sparing nontransformed human and mouse embryonic fibroblasts in vitro. Finally, treatment with AZD6738 induced apoptosis and regression of human neuroblastoma and medulloblastoma tumors engrafted in immunodeficient mice in vivo. This effect was potentiated by combined treatment with cisplatin, including substantial antitumor activity against patient-derived primary neuroblastoma xenografts. These findings delineate a therapeutically actionable synthetic dependency induced in PGBD5-expressing solid tumors.
尽管付出了巨大努力，但儿童和成人实体瘤的治愈率仍不尽如人意。对强化化疗的耐药性很常见，而分子治疗的靶点在很大程度上尚未确定。我们发现，大多数儿童实体瘤，包括横纹肌肉瘤、神经母细胞瘤、髓母细胞瘤和尤文肉瘤，都表达一种活跃的 DNA 转座酶 ，它可以促进人细胞中的特定基因组重排。我们通过功能遗传方法发现，缺乏非同源末端连接（NHEJ）DNA 修复的小鼠和人细胞不能耐受 PGBD5 的表达。在 DNA 损伤信号抑制剂的化学筛选中，我们鉴定出 AZD6738 是 PGBD5 依赖性 DNA 损伤和细胞凋亡的特异性敏化剂。我们发现 PGBD5 的表达，但不是其核酸酶活性缺陷突变体的表达，足以诱导对 AZD6738 的敏感性。内源性 PGBD5 的耗竭赋予了人肿瘤细胞对 AZD6738 的耐药性。PGBD5 表达的肿瘤细胞在 AZD6738 处理后积累未修复的 DNA 损伤，并在没有立即 DNA 复制应激的情况下，在有丝分裂和 G1 期细胞中发生凋亡。因此，AZD6738 对大多数神经母细胞瘤、髓母细胞瘤、尤文肉瘤和横纹肌肉瘤细胞表现出纳摩尔效力，而在体外对未转化的人和小鼠胚胎成纤维细胞具有选择性。最后，AZD6738 处理在体内诱导免疫缺陷小鼠移植的人神经母细胞瘤和髓母细胞瘤肿瘤的凋亡和消退。联合顺铂治疗可增强这种作用，包括对患者来源的原发性神经母细胞瘤异种移植物的实质性抗肿瘤活性。这些发现描绘了在 PGBD5 表达的实体瘤中诱导的一种可治疗的合成依赖性。
