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The mechanism and clinical application of DNA damage repair inhibitors combined with immune checkpoint inhibitors in the treatment of urologic cancer

Urologic cancers such as kidney, bladder, prostate, and uroepithelial cancers have recently become a considerable global health burden, and the response to immunotherapy is limited due to immune escape and immune resistance. Therefore, it is crucial to find appropriate and effective combination ther...

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Autores principales: Xie, Deqian, Jiang, Bowen, Wang, Shijin, Wang, Qifei, Wu, Guangzhen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10248030/
https://www.ncbi.nlm.nih.gov/pubmed/37305685
http://dx.doi.org/10.3389/fcell.2023.1200466
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author Xie, Deqian
Jiang, Bowen
Wang, Shijin
Wang, Qifei
Wu, Guangzhen
author_facet Xie, Deqian
Jiang, Bowen
Wang, Shijin
Wang, Qifei
Wu, Guangzhen
author_sort Xie, Deqian
collection PubMed
description Urologic cancers such as kidney, bladder, prostate, and uroepithelial cancers have recently become a considerable global health burden, and the response to immunotherapy is limited due to immune escape and immune resistance. Therefore, it is crucial to find appropriate and effective combination therapies to improve the sensitivity of patients to immunotherapy. DNA damage repair inhibitors can enhance the immunogenicity of tumor cells by increasing tumor mutational burden and neoantigen expression, activating immune-related signaling pathways, regulating PD-L1 expression, and reversing the immunosuppressive tumor microenvironment to activate the immune system and enhance the efficacy of immunotherapy. Based on promising experimental results from preclinical studies, many clinical trials combining DNA damage repair inhibitors (e.g., PARP inhibitors and ATR inhibitors) with immune checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitors) are underway in patients with urologic cancers. Results from several clinical trials have shown that the combination of DNA damage repair inhibitors with immune checkpoint inhibitors can improve objective rates, progression-free survival, and overall survival (OS) in patients with urologic tumors, especially in patients with defective DNA damage repair genes or a high mutational load. In this review, we present the results of preclinical and clinical trials of different DNA damage repair inhibitors in combination with immune checkpoint inhibitors in urologic cancers and summarize the potential mechanism of action of the combination therapy. Finally, we also discuss the challenges of dose toxicity, biomarker selection, drug tolerance, drug interactions in the treatment of urologic tumors with this combination therapy and look into the future direction of this combination therapy.
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spelling pubmed-102480302023-06-09 The mechanism and clinical application of DNA damage repair inhibitors combined with immune checkpoint inhibitors in the treatment of urologic cancer Xie, Deqian Jiang, Bowen Wang, Shijin Wang, Qifei Wu, Guangzhen Front Cell Dev Biol Cell and Developmental Biology Urologic cancers such as kidney, bladder, prostate, and uroepithelial cancers have recently become a considerable global health burden, and the response to immunotherapy is limited due to immune escape and immune resistance. Therefore, it is crucial to find appropriate and effective combination therapies to improve the sensitivity of patients to immunotherapy. DNA damage repair inhibitors can enhance the immunogenicity of tumor cells by increasing tumor mutational burden and neoantigen expression, activating immune-related signaling pathways, regulating PD-L1 expression, and reversing the immunosuppressive tumor microenvironment to activate the immune system and enhance the efficacy of immunotherapy. Based on promising experimental results from preclinical studies, many clinical trials combining DNA damage repair inhibitors (e.g., PARP inhibitors and ATR inhibitors) with immune checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitors) are underway in patients with urologic cancers. Results from several clinical trials have shown that the combination of DNA damage repair inhibitors with immune checkpoint inhibitors can improve objective rates, progression-free survival, and overall survival (OS) in patients with urologic tumors, especially in patients with defective DNA damage repair genes or a high mutational load. In this review, we present the results of preclinical and clinical trials of different DNA damage repair inhibitors in combination with immune checkpoint inhibitors in urologic cancers and summarize the potential mechanism of action of the combination therapy. Finally, we also discuss the challenges of dose toxicity, biomarker selection, drug tolerance, drug interactions in the treatment of urologic tumors with this combination therapy and look into the future direction of this combination therapy. Frontiers Media S.A. 2023-05-25 /pmc/articles/PMC10248030/ /pubmed/37305685 http://dx.doi.org/10.3389/fcell.2023.1200466 Text en Copyright © 2023 Xie, Jiang, Wang, Wang and Wu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Xie, Deqian
Jiang, Bowen
Wang, Shijin
Wang, Qifei
Wu, Guangzhen
The mechanism and clinical application of DNA damage repair inhibitors combined with immune checkpoint inhibitors in the treatment of urologic cancer
title The mechanism and clinical application of DNA damage repair inhibitors combined with immune checkpoint inhibitors in the treatment of urologic cancer
title_full The mechanism and clinical application of DNA damage repair inhibitors combined with immune checkpoint inhibitors in the treatment of urologic cancer
title_fullStr The mechanism and clinical application of DNA damage repair inhibitors combined with immune checkpoint inhibitors in the treatment of urologic cancer
title_full_unstemmed The mechanism and clinical application of DNA damage repair inhibitors combined with immune checkpoint inhibitors in the treatment of urologic cancer
title_short The mechanism and clinical application of DNA damage repair inhibitors combined with immune checkpoint inhibitors in the treatment of urologic cancer
title_sort mechanism and clinical application of dna damage repair inhibitors combined with immune checkpoint inhibitors in the treatment of urologic cancer
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10248030/
https://www.ncbi.nlm.nih.gov/pubmed/37305685
http://dx.doi.org/10.3389/fcell.2023.1200466
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