Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.
The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, and the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Mol Cancer Ther. 2019 Nov;18(11):1899-1908. doi: 10.1158/1535-7163.MCT-19-0208.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid malignancies with very few therapeutic options to treat advanced or metastatic disease. The utilization of genomic sequencing has identified therapeutically relevant alterations in approximately 25% of PDAC patients, most notably in the DNA damage response and repair (DDR) genes, rendering cancer cells more sensitive to DNA-damaging agents and to DNA damage response inhibitors, such as PARP inhibitors. ATM is one of the most commonly mutated DDR genes, with somatic mutations identified in 2% to 18% of PDACs and germline mutations identified in 1% to 34% of PDACs. ATM plays a complex role as a cell-cycle checkpoint kinase, regulator of a wide array of downstream proteins, and responder to DNA damage for genome stability. The disruption of ATM signaling leads to downstream reliance on ATR and CHK1, among other DNA-repair mechanisms, which may enable exploiting the inhibition of downstream proteins as therapeutic targets in -mutated PDACs. In this review, we detail the function of ATM, review the current data on ATM deficiency in PDAC, examine the therapeutic implications of ATM alterations, and explore the current clinical trials surrounding the ATM pathway.
胰腺导管腺癌（PDAC）仍然是最致命的实体恶性肿瘤之一，对于晚期或转移性疾病，治疗选择非常有限。基因组测序的应用已经确定了大约 25%的 PDAC 患者具有治疗相关的改变，最显著的是在 DNA 损伤反应和修复（DDR）基因中，使癌细胞对 DNA 损伤剂和 DNA 损伤反应抑制剂（如 PARP 抑制剂）更敏感。ATM 是最常见的突变 DDR 基因之一，在 2%至 18%的 PDAC 中发现了体细胞突变，在 1%至 34%的 PDAC 中发现了种系突变。ATM 作为细胞周期检查点激酶、广泛下游蛋白的调节剂以及基因组稳定性的 DNA 损伤应答者，发挥着复杂的作用。ATM 信号的中断导致下游对 ATR 和 CHK1 的依赖，以及其他 DNA 修复机制，这可能使我们能够利用下游蛋白的抑制作为 -突变 PDAC 的治疗靶点。在这篇综述中，我们详细描述了 ATM 的功能，回顾了 PDAC 中 ATM 缺陷的现有数据，研究了 ATM 改变的治疗意义，并探讨了围绕 ATM 途径的当前临床试验。
