胰腺导管腺癌 (PDAC) 是所有恶性肿瘤中预后最不良的一种。在这篇综述中，我们研究了针对 DNA 损伤反应 (DDR) 途径关键调节因子的抑制剂的作用，无论是作为单一治疗还是与化疗药物和 PDAC 靶向治疗联合治疗。 PARP 抑制剂单一疗法最显着的临床益处与携带 BRCA1/2 和其他 DDR 基因突变作为预测生物标志物的个体的合成致死原理相关。此外，用RTK抑制剂诱导BRCA，包括VEGFR和c-MET及其下游信号通路、RAS/RAF/MEK/ERK和PI3K/AKT/mTOR，以扩大PARP抑制剂在无DDR突变患者中的应用，也已得到解决。 PARP 抑制剂之外的其他 DDR 靶向药物，包括 ATM、ATR、CHEK1/2 和 WEE1 抑制剂，也已在 PDAC 临床前模型中证明了其潜力，并可能在未来的研究中带来希望。版权所有 © 2024 Elsevier B.V。保留所有权利。

Pancreatic ductal adenocarcinoma (PDAC) is associated with one of the most unfavorable prognoses across all malignancies. In this review, we investigate the role of inhibitors targeting crucial regulators of DNA damage response (DDR) pathways, either as single treatments or in combination with chemotherapeutic agents and targeted therapies in PDAC. The most prominent clinical benefit of PARP inhibitors' monotherapy is related to the principle of synthetic lethality in individuals harboring BRCA1/2 and other DDR gene mutations as predictive biomarkers. Moreover, induction of BRCAness with inhibitors of RTKs, including VEGFR and c-MET and their downstream signaling pathways, RAS/RAF/MEK/ERK and PI3K/AKT/mTOR in order to expand the application of PARP inhibitors in patients without DDR mutations, has also been addressed. Other DDR-targeting agents beyond PARP inhibitors, including inhibitors of ATM, ATR, CHEK1/2, and WEE1 have also demonstrated their potential in preclinical models of PDAC and may hold promise in future studies.Copyright © 2024 Elsevier B.V. All rights reserved.