1. Targeting DNA damage response in pancreatic ductal adenocarcinoma: A review of preclinical and clinical evidence.
- Author
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Moosavi F, Hassani B, Nazari S, Saso L, and Firuzi O
- 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., Competing Interests: Declaration of competing interest The authors declare that they do not possess any identifiable competing financial interests or personal relationships that might be perceived to have impacted the research presented in this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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