A subset of cancers across multiple histologies with predominantly poor outcomes use the alternative lengthening of telomeres (ALT) mechanism to maintain telomere length, which can be identified with robust biomarkers. ALT has been reported to be prevalent in high-risk neuroblastoma and certain sarcomas, and ALT cancers are a major clinical challenge that lack targeted therapeutic approaches. Here, we found ALT in a variety of pediatric and adult cancer histologies, including carcinomas. Patient-derived ALT cancer cell lines from neuroblastomas, sarcomas, and carcinomas were hypersensitive to the p53 reactivator eprenetapopt (APR-246) relative to telomerase-positive (TA+) models. Constitutive telomere damage signaling in ALT cells activated ataxia-telangiectasia mutated (ATM) kinase to phosphorylate p53, which resulted in selective ALT sensitivity to APR-246. Treatment with APR-246 combined with irinotecan achieved complete responses in mice xenografted with ALT neuroblastoma, rhabdomyosarcoma, and breast cancer and delayed tumor growth in ALT colon cancer xenografts, while the combination had limited efficacy in TA+ tumor models. A large number of adult and pediatric cancers present with the ALT phenotype, which confers a uniquely high sensitivity to reactivation of p53. These data support clinical evaluation of a combinatorial approach using APR-246 and irinotecan in ALT patients with cancer. Significance: This work demonstrates that constitutive activation of ATM in chemotherapy-refractory ALT cancer cells renders them hypersensitive to reactivation of p53 function by APR-246, indicating a potential strategy to overcome therapeutic resistance.

中文翻译：

---

癌症中端粒的选择性延长导致 p53 功能重新激活的脆弱性

跨多种组织学且预后较差的癌症子集使用端粒替代延长 (ALT) 机制来维持端粒长度，这可以通过强大的生物标志物进行识别。据报道，ALT 在高危神经母细胞瘤和某些肉瘤中普遍存在，而 ALT 癌症是缺乏针对性治疗方法的重大临床挑战。在这里，我们在各种儿童和成人癌症组织学中发现了 ALT，包括癌症。相对于端粒酶阳性 (TA+) 模型，来自神经母细胞瘤、肉瘤和癌的患者来源的 ALT 癌细胞系对 p53 重新激活剂 eprenetapopt (APR-246) 过敏。ALT 细胞中的组成性端粒损伤信号激活共济失调毛细血管扩张突变 (ATM) 激酶以磷酸化 p53，这导致了 ALT 对 APR-246 的选择性敏感性。APR-246 联合伊立替康治疗在 ALT 神经母细胞瘤、横纹肌肉瘤和乳腺癌异种移植小鼠中实现了完全缓解，并延迟了 ALT 结肠癌异种移植物中的肿瘤生长，而该组合在 TA+ 肿瘤模型中疗效有限。许多成人和儿童癌症都具有 ALT 表型，这赋予了 p53 重新激活独特的高敏感性。这些数据支持对 ALT 癌症患者使用 APR-246 和伊立替康的组合方法进行临床评估。意义：这项工作表明，化疗难治性 ALT 癌细胞中 ATM 的组成性激活使它们对 APR-246 重新激活 p53 功能高度敏感，这表明了克服治疗耐药性的潜在策略。