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DNA Damage Repair Deficiency in Pancreatic Ductal Adenocarcinoma: Preclinical Models and Clinical Perspectives

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide, and survival rates have barely improved in decades. In the era of precision medicine, treatment strategies tailored to disease mutations have revolutionized cancer therapy. Next generation sequencing has found that...

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Autores principales: Stoof, Jojanneke, Harrold, Emily, Mariottino, Sarah, Lowery, Maeve A., Walsh, Naomi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546202/
https://www.ncbi.nlm.nih.gov/pubmed/34712667
http://dx.doi.org/10.3389/fcell.2021.749490
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author Stoof, Jojanneke
Harrold, Emily
Mariottino, Sarah
Lowery, Maeve A.
Walsh, Naomi
author_facet Stoof, Jojanneke
Harrold, Emily
Mariottino, Sarah
Lowery, Maeve A.
Walsh, Naomi
author_sort Stoof, Jojanneke
collection PubMed
description Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide, and survival rates have barely improved in decades. In the era of precision medicine, treatment strategies tailored to disease mutations have revolutionized cancer therapy. Next generation sequencing has found that up to a third of all PDAC tumors contain deleterious mutations in DNA damage repair (DDR) genes, highlighting the importance of these genes in PDAC. The mechanisms by which DDR gene mutations promote tumorigenesis, therapeutic response, and subsequent resistance are still not fully understood. Therefore, an opportunity exists to elucidate these processes and to uncover relevant therapeutic drug combinations and strategies to target DDR deficiency in PDAC. However, a constraint to preclinical research is due to limitations in appropriate laboratory experimental models. Models that effectively recapitulate their original cancer tend to provide high levels of predictivity and effective translation of preclinical findings to the clinic. In this review, we outline the occurrence and role of DDR deficiency in PDAC and provide an overview of clinical trials that target these pathways and the preclinical models such as 2D cell lines, 3D organoids and mouse models [genetically engineered mouse model (GEMM), and patient-derived xenograft (PDX)] used in PDAC DDR deficiency research.
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spelling pubmed-85462022021-10-27 DNA Damage Repair Deficiency in Pancreatic Ductal Adenocarcinoma: Preclinical Models and Clinical Perspectives Stoof, Jojanneke Harrold, Emily Mariottino, Sarah Lowery, Maeve A. Walsh, Naomi Front Cell Dev Biol Cell and Developmental Biology Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide, and survival rates have barely improved in decades. In the era of precision medicine, treatment strategies tailored to disease mutations have revolutionized cancer therapy. Next generation sequencing has found that up to a third of all PDAC tumors contain deleterious mutations in DNA damage repair (DDR) genes, highlighting the importance of these genes in PDAC. The mechanisms by which DDR gene mutations promote tumorigenesis, therapeutic response, and subsequent resistance are still not fully understood. Therefore, an opportunity exists to elucidate these processes and to uncover relevant therapeutic drug combinations and strategies to target DDR deficiency in PDAC. However, a constraint to preclinical research is due to limitations in appropriate laboratory experimental models. Models that effectively recapitulate their original cancer tend to provide high levels of predictivity and effective translation of preclinical findings to the clinic. In this review, we outline the occurrence and role of DDR deficiency in PDAC and provide an overview of clinical trials that target these pathways and the preclinical models such as 2D cell lines, 3D organoids and mouse models [genetically engineered mouse model (GEMM), and patient-derived xenograft (PDX)] used in PDAC DDR deficiency research. Frontiers Media S.A. 2021-10-12 /pmc/articles/PMC8546202/ /pubmed/34712667 http://dx.doi.org/10.3389/fcell.2021.749490 Text en Copyright © 2021 Stoof, Harrold, Mariottino, Lowery and Walsh. 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
Stoof, Jojanneke
Harrold, Emily
Mariottino, Sarah
Lowery, Maeve A.
Walsh, Naomi
DNA Damage Repair Deficiency in Pancreatic Ductal Adenocarcinoma: Preclinical Models and Clinical Perspectives
title DNA Damage Repair Deficiency in Pancreatic Ductal Adenocarcinoma: Preclinical Models and Clinical Perspectives
title_full DNA Damage Repair Deficiency in Pancreatic Ductal Adenocarcinoma: Preclinical Models and Clinical Perspectives
title_fullStr DNA Damage Repair Deficiency in Pancreatic Ductal Adenocarcinoma: Preclinical Models and Clinical Perspectives
title_full_unstemmed DNA Damage Repair Deficiency in Pancreatic Ductal Adenocarcinoma: Preclinical Models and Clinical Perspectives
title_short DNA Damage Repair Deficiency in Pancreatic Ductal Adenocarcinoma: Preclinical Models and Clinical Perspectives
title_sort dna damage repair deficiency in pancreatic ductal adenocarcinoma: preclinical models and clinical perspectives
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546202/
https://www.ncbi.nlm.nih.gov/pubmed/34712667
http://dx.doi.org/10.3389/fcell.2021.749490
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