Affiliation:
1. Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu 514-8507, Japan
Abstract
Cancer cells frequently exhibit defects in DNA damage repair (DDR), leading to genomic instability. Mutations in DDR genes or epigenetic alterations leading to the downregulation of DDR genes can result in increased dependency on other DDR pathways. Therefore, DDR pathways could be a treatment target for various cancers. In fact, polyadenosine diphosphatase ribose polymerase (PARP) inhibitors, such as olaparib (Lynparza®), have shown remarkable therapeutic efficacy against BRCA1/2-mutant cancers through synthetic lethality. Recent genomic analytical advancements have revealed that BRCA1/BRCA2 pathogenic variants are the most frequent mutations among DDR genes in prostate cancer. Currently, the PROfound randomized controlled trial is investigating the efficacy of a PARP inhibitor, olaparib (Lynparza®), in patients with metastatic castration-resistant prostate cancer (mCRPC). The efficacy of the drug is promising, especially in patients with BRCA1/BRCA2 pathogenic variants, even if they are in the advanced stage of the disease. However, olaparib (Lynparza®) is not effective in all BRCA1/2 mutant prostate cancer patients and inactivation of DDR genes elicits genomic instability, leading to alterations in multiple genes, which eventually leads to drug resistance. In this review, we summarize PARP inhibitors’ basic and clinical mechanisms of action against prostate cancer cells and discuss their effects on the tumor microenvironment.
Reference57 articles.
1. Breast Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology;Gradishar;J. Natl. Compr. Cancer Netw.,2022
2. Non-Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology;Ettinger;J. Natl. Compr. Cancer Netw.,2022
3. NCCN Guidelines® Insights: Prostate Cancer, Version 1.2023;Schaeffer;J. Natl. Compr. Cancer Netw.,2022
4. Olaparib for Metastatic Castration-Resistant Prostate Cancer;Mateo;N. Engl. J. Med.,2020
5. Targeting DNA damage response pathways in cancer;Groelly;Nat. Rev. Cancer,2023
Cited by
3 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献