Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Danish Cancer Institute, Copenhagen, Denmark.
Sci Adv. 2023 Nov 24;9(47):eadg2263. doi: 10.1126/sciadv.adg2263. Epub 2023 Nov 22.
Ataxia-telangiectasia mutated (ATM) plays a central role in the cellular response to DNA damage and ATM alterations are common in several tumor types including bladder cancer. However, the specific impact of ATM alterations on therapy response in bladder cancer is uncertain. Here, we combine preclinical modeling and clinical analyses to comprehensively define the impact of ATM alterations on bladder cancer. We show that ATM loss is sufficient to increase sensitivity to DNA-damaging agents including cisplatin and radiation. Furthermore, ATM loss drives sensitivity to DNA repair-targeted agents including poly(ADP-ribose) polymerase (PARP) and Ataxia telangiectasia and Rad3 related (ATR) inhibitors. ATM loss alters the immune microenvironment and improves anti-PD1 response in preclinical bladder models but is not associated with improved anti-PD1/PD-L1 response in clinical cohorts. Last, we show that ATM expression by immunohistochemistry is strongly correlated with response to chemoradiotherapy. Together, these data define a potential role for ATM as a predictive biomarker in bladder cancer.
共济失调毛细血管扩张突变基因（ATM）在细胞对 DNA 损伤的反应中起核心作用，ATM 改变在包括膀胱癌在内的几种肿瘤类型中很常见。然而，ATM 改变对膀胱癌治疗反应的具体影响尚不确定。在这里，我们结合临床前模型和临床分析，全面定义 ATM 改变对膀胱癌的影响。我们表明，ATM 缺失足以增加对包括顺铂和辐射在内的 DNA 损伤剂的敏感性。此外，ATM 缺失导致对包括聚（ADP-核糖）聚合酶（PARP）和共济失调毛细血管扩张和 Rad3 相关（ATR）抑制剂在内的 DNA 修复靶向药物的敏感性。ATM 缺失改变了免疫微环境，并改善了临床前膀胱癌模型中抗 PD-1 反应，但与临床队列中抗 PD-1/PD-L1 反应的改善无关。最后，我们表明免疫组织化学检测到的 ATM 表达与放化疗反应密切相关。总之，这些数据定义了 ATM 在膀胱癌中作为预测生物标志物的潜在作用。
