Oncol Res Treat. 2018;41(10):619-625. doi: 10.1159/000493401. Epub 2018 Sep 28.
Pancreatic cancer is one of the most common causes of cancer-related mortality in the Western world and pancreatic ductal adenocarcinoma (PDAC) is by far the most common pancreatic cancer entity. Locally advanced or metastatic PDAC remains a major clinical challenge, and the prognosis of affected patients is dismal despite substantial research efforts in this area. Recent large-scale genomic analyses of PDAC revealed that KRAS is the most frequently mutated driver gene in this entity. In addition, a relatively large proportion of PDAC patients displays germline variants in genes involved in DNA repair, particularly DNA double-strand repair. Similarly, a sizable fraction of sporadic PDAC cases harbor mutations in genome maintenance genes, such as BRCA1, BRCA2, and ATM. While direct targeting of oncogenic KRAS is currently not possible in the clinical setting, these defects in DNA repair may open new therapeutic avenues. Here, we discuss the potential use of compounds that interfere with DNA repair and genome maintenance mechanisms for the treatment of PDAC. We particularly focus on the genotype-tailored use of compounds, such as PARP inhibitors, as well as ATR- and DNA-protein kinase catalytic subunit (PKcs) inhibitors.
胰腺癌是西方世界癌症相关死亡的最常见原因之一，而胰腺导管腺癌（PDAC）是迄今为止最常见的胰腺癌实体瘤。局部晚期或转移性 PDAC 仍然是一个主要的临床挑战，尽管在该领域进行了大量的研究，但受影响患者的预后仍然很差。最近对 PDAC 的大规模基因组分析显示，KRAS 是该实体中最常见的突变驱动基因。此外，相当一部分 PDAC 患者携带参与 DNA 修复的基因中的种系变异，特别是 DNA 双链修复。同样，相当一部分散发性 PDAC 病例中存在基因组维持基因（如 BRCA1、BRCA2 和 ATM）的突变。虽然目前在临床环境中不可能直接靶向致癌性 KRAS，但这些 DNA 修复缺陷可能开辟新的治疗途径。在这里，我们讨论了干扰 DNA 修复和基因组维持机制的化合物在治疗 PDAC 中的潜在用途。我们特别关注化合物的基于基因型的使用，如 PARP 抑制剂，以及 ATR 和 DNA 蛋白激酶催化亚基（PKcs）抑制剂。
