Targeting DNA damage response in pancreatic ductal adenocarcinoma: A review of preclinical and clinical evidence

IF 11.3 1区化学 Q1 CHEMISTRY, PHYSICAL

ACS Catalysis Pub Date : 2024-09-24 DOI:10.1016/j.bbcan.2024.189185

Fatemeh Moosavi , Bahareh Hassani , Somayeh Nazari , Luciano Saso , Omidreza Firuzi

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引用次数: 0

Abstract

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.

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针对胰腺导管腺癌的 DNA 损伤反应：临床前和临床证据综述。

胰腺导管腺癌（PDAC）是所有恶性肿瘤中预后最差的一种。在这篇综述中，我们研究了针对 DNA 损伤应答（DDR）通路关键调控因子的抑制剂在 PDAC 中作为单一疗法或与化疗药物和靶向疗法联合使用所发挥的作用。PARP抑制剂单药治疗最突出的临床疗效与作为预测性生物标志物的BRCA1/2和其他DDR基因突变个体的合成致死原则有关。此外，为了扩大 PARP 抑制剂在无 DDR 基因突变患者中的应用，还研究了用 RTK 抑制剂诱导 BRCAness，包括 VEGFR 和 c-MET 及其下游信号通路 RAS/RAF/MEK/ERK 和 PI3K/AKT/mTOR。PARP 抑制剂之外的其他 DDR 靶向药物，包括 ATM、ATR、CHEK1/2 和 WEE1 的抑制剂，也已在 PDAC 的临床前模型中证明了其潜力，并可能在未来的研究中大有可为。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Catalysis CHEMISTRY, PHYSICAL-

CiteScore

20.80

自引率

6.20%

发文量

1253

审稿时长

1.5 months

期刊介绍： ACS Catalysis is an esteemed journal that publishes original research in the fields of heterogeneous catalysis, molecular catalysis, and biocatalysis. It offers broad coverage across diverse areas such as life sciences, organometallics and synthesis, photochemistry and electrochemistry, drug discovery and synthesis, materials science, environmental protection, polymer discovery and synthesis, and energy and fuels. The scope of the journal is to showcase innovative work in various aspects of catalysis. This includes new reactions and novel synthetic approaches utilizing known catalysts, the discovery or modification of new catalysts, elucidation of catalytic mechanisms through cutting-edge investigations, practical enhancements of existing processes, as well as conceptual advances in the field. Contributions to ACS Catalysis can encompass both experimental and theoretical research focused on catalytic molecules, macromolecules, and materials that exhibit catalytic turnover.