{"title":"揭示存在同源重组修复缺陷的前列腺癌对 PARP 抑制剂耐药性的分子基础。","authors":"Nabila Zaman, Atar Singh Kushwah, Anagha Badriprasad, Goutam Chakraborty","doi":"10.1016/bs.ircmb.2024.03.004","DOIUrl":null,"url":null,"abstract":"<p><p>Prostate cancer is a disease with heterogeneous characteristics, making its treatability and curability dependent on the cancer's stage. While prostate cancer is often indolent, some cases can be aggressive and evolve into metastatic castration-resistant prostate cancer (mCRPC), which is lethal. A significant subset of individuals with mCRPC exhibit germline and somatic variants in components of the DNA damage repair (DDR) pathway. Recently, PARP inhibitors (PARPi) have shown promise in treating mCRPC patients who carry deleterious alterations in BRCA2 and 13 other DDR genes that are important for the homologous recombination repair (HRR) pathway. These inhibitors function by trapping PARP, resulting in impaired PARP activity and increased DNA damage, ultimately leading to cell death through synthetic lethality. However, the response to these inhibitors only lasts for 3-4 months, after which the cancer becomes PARPi resistant. Cancer cells can develop resistance to PARPi through numerous mechanisms, such as secondary reversion mutations in DNA repair pathway genes, heightened drug efflux, loss of PARP expression, HRR reactivation, replication fork stability, and upregulation of Wnt/Catenin and ABCB1 pathways. Overcoming PARPi resistance is a critical and complex process, and there are two possible ways to sensitize the resistance. The first approach is to potentiate the PARPi agents through chemo/radiotherapy and combination therapy, while the second approach entails targeting different signaling pathways. This review article highlights the latest evidence on the resistance mechanism of PARPi in lethal prostate cancer and discusses additional therapeutic opportunities available for prostate cancer patients with DDR gene alterations who do not respond to PARPi.</p>","PeriodicalId":14422,"journal":{"name":"International review of cell and molecular biology","volume":"389 ","pages":"257-301"},"PeriodicalIF":0.0000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Unravelling the molecular basis of PARP inhibitor resistance in prostate cancer with homologous recombination repair deficiency.\",\"authors\":\"Nabila Zaman, Atar Singh Kushwah, Anagha Badriprasad, Goutam Chakraborty\",\"doi\":\"10.1016/bs.ircmb.2024.03.004\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Prostate cancer is a disease with heterogeneous characteristics, making its treatability and curability dependent on the cancer's stage. While prostate cancer is often indolent, some cases can be aggressive and evolve into metastatic castration-resistant prostate cancer (mCRPC), which is lethal. A significant subset of individuals with mCRPC exhibit germline and somatic variants in components of the DNA damage repair (DDR) pathway. Recently, PARP inhibitors (PARPi) have shown promise in treating mCRPC patients who carry deleterious alterations in BRCA2 and 13 other DDR genes that are important for the homologous recombination repair (HRR) pathway. These inhibitors function by trapping PARP, resulting in impaired PARP activity and increased DNA damage, ultimately leading to cell death through synthetic lethality. However, the response to these inhibitors only lasts for 3-4 months, after which the cancer becomes PARPi resistant. Cancer cells can develop resistance to PARPi through numerous mechanisms, such as secondary reversion mutations in DNA repair pathway genes, heightened drug efflux, loss of PARP expression, HRR reactivation, replication fork stability, and upregulation of Wnt/Catenin and ABCB1 pathways. Overcoming PARPi resistance is a critical and complex process, and there are two possible ways to sensitize the resistance. The first approach is to potentiate the PARPi agents through chemo/radiotherapy and combination therapy, while the second approach entails targeting different signaling pathways. This review article highlights the latest evidence on the resistance mechanism of PARPi in lethal prostate cancer and discusses additional therapeutic opportunities available for prostate cancer patients with DDR gene alterations who do not respond to PARPi.</p>\",\"PeriodicalId\":14422,\"journal\":{\"name\":\"International review of cell and molecular biology\",\"volume\":\"389 \",\"pages\":\"257-301\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International review of cell and molecular biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1016/bs.ircmb.2024.03.004\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/3/31 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"Biochemistry, Genetics and Molecular Biology\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International review of cell and molecular biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/bs.ircmb.2024.03.004","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/3/31 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}
Unravelling the molecular basis of PARP inhibitor resistance in prostate cancer with homologous recombination repair deficiency.
Prostate cancer is a disease with heterogeneous characteristics, making its treatability and curability dependent on the cancer's stage. While prostate cancer is often indolent, some cases can be aggressive and evolve into metastatic castration-resistant prostate cancer (mCRPC), which is lethal. A significant subset of individuals with mCRPC exhibit germline and somatic variants in components of the DNA damage repair (DDR) pathway. Recently, PARP inhibitors (PARPi) have shown promise in treating mCRPC patients who carry deleterious alterations in BRCA2 and 13 other DDR genes that are important for the homologous recombination repair (HRR) pathway. These inhibitors function by trapping PARP, resulting in impaired PARP activity and increased DNA damage, ultimately leading to cell death through synthetic lethality. However, the response to these inhibitors only lasts for 3-4 months, after which the cancer becomes PARPi resistant. Cancer cells can develop resistance to PARPi through numerous mechanisms, such as secondary reversion mutations in DNA repair pathway genes, heightened drug efflux, loss of PARP expression, HRR reactivation, replication fork stability, and upregulation of Wnt/Catenin and ABCB1 pathways. Overcoming PARPi resistance is a critical and complex process, and there are two possible ways to sensitize the resistance. The first approach is to potentiate the PARPi agents through chemo/radiotherapy and combination therapy, while the second approach entails targeting different signaling pathways. This review article highlights the latest evidence on the resistance mechanism of PARPi in lethal prostate cancer and discusses additional therapeutic opportunities available for prostate cancer patients with DDR gene alterations who do not respond to PARPi.
期刊介绍:
International Review of Cell and Molecular Biology presents current advances and comprehensive reviews in cell biology-both plant and animal. Articles address structure and control of gene expression, nucleocytoplasmic interactions, control of cell development and differentiation, and cell transformation and growth. Authored by some of the foremost scientists in the field, each volume provides up-to-date information and directions for future research.