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Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

SIMPLE SUMMARY: A subset of patients with pancreatic cancer demonstrate heightened response rates and prolonged survival to platinum chemotherapy and PARP inhibitors. Deficient homologous recombination (HR), a critical DNA repair program, is a major driver of this susceptibility. Furthermore, the cl...

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Autores principales: Wattenberg, Max M., Reiss, Kim A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466888/
https://www.ncbi.nlm.nih.gov/pubmed/34572943
http://dx.doi.org/10.3390/cancers13184716
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author Wattenberg, Max M.
Reiss, Kim A.
author_facet Wattenberg, Max M.
Reiss, Kim A.
author_sort Wattenberg, Max M.
collection PubMed
description SIMPLE SUMMARY: A subset of patients with pancreatic cancer demonstrate heightened response rates and prolonged survival to platinum chemotherapy and PARP inhibitors. Deficient homologous recombination (HR), a critical DNA repair program, is a major driver of this susceptibility. Furthermore, the clinical impact of mutations in distinct HR genes is variable and is modified by diverse tumor intrinsic and extrinsic factors. In this review, we discuss the determinants of homologous recombination deficiency (HRD) in pancreatic cancer. We also highlight emerging methods for identifying and inducing HRD in cancer. ABSTRACT: Pancreatic cancer is a treatment-resistant malignancy associated with high mortality. However, defective homologous recombination (HR), a DNA repair mechanism required for high-fidelity repair of double-strand DNA breaks, is a therapeutic vulnerability. Consistent with this, a subset of patients with pancreatic cancer show unique tumor responsiveness to HR-dependent DNA damage triggered by certain treatments (platinum chemotherapy and PARP inhibitors). While pathogenic mutations in HR genes are a major driver of this sensitivity, another layer of diverse tumor intrinsic and extrinsic factors regulate the HR deficiency (HRD) phenotype. Defining the mechanisms that drive HRD may guide the development of novel strategies and therapeutics to induce treatment sensitivity in non-HRD tumors. Here, we discuss the complexity underlying HRD in pancreatic cancer and highlight implications for identifying and treating this distinct subset of patients.
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spelling pubmed-84668882021-09-27 Determinants of Homologous Recombination Deficiency in Pancreatic Cancer Wattenberg, Max M. Reiss, Kim A. Cancers (Basel) Review SIMPLE SUMMARY: A subset of patients with pancreatic cancer demonstrate heightened response rates and prolonged survival to platinum chemotherapy and PARP inhibitors. Deficient homologous recombination (HR), a critical DNA repair program, is a major driver of this susceptibility. Furthermore, the clinical impact of mutations in distinct HR genes is variable and is modified by diverse tumor intrinsic and extrinsic factors. In this review, we discuss the determinants of homologous recombination deficiency (HRD) in pancreatic cancer. We also highlight emerging methods for identifying and inducing HRD in cancer. ABSTRACT: Pancreatic cancer is a treatment-resistant malignancy associated with high mortality. However, defective homologous recombination (HR), a DNA repair mechanism required for high-fidelity repair of double-strand DNA breaks, is a therapeutic vulnerability. Consistent with this, a subset of patients with pancreatic cancer show unique tumor responsiveness to HR-dependent DNA damage triggered by certain treatments (platinum chemotherapy and PARP inhibitors). While pathogenic mutations in HR genes are a major driver of this sensitivity, another layer of diverse tumor intrinsic and extrinsic factors regulate the HR deficiency (HRD) phenotype. Defining the mechanisms that drive HRD may guide the development of novel strategies and therapeutics to induce treatment sensitivity in non-HRD tumors. Here, we discuss the complexity underlying HRD in pancreatic cancer and highlight implications for identifying and treating this distinct subset of patients. MDPI 2021-09-21 /pmc/articles/PMC8466888/ /pubmed/34572943 http://dx.doi.org/10.3390/cancers13184716 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Wattenberg, Max M.
Reiss, Kim A.
Determinants of Homologous Recombination Deficiency in Pancreatic Cancer
title Determinants of Homologous Recombination Deficiency in Pancreatic Cancer
title_full Determinants of Homologous Recombination Deficiency in Pancreatic Cancer
title_fullStr Determinants of Homologous Recombination Deficiency in Pancreatic Cancer
title_full_unstemmed Determinants of Homologous Recombination Deficiency in Pancreatic Cancer
title_short Determinants of Homologous Recombination Deficiency in Pancreatic Cancer
title_sort determinants of homologous recombination deficiency in pancreatic cancer
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466888/
https://www.ncbi.nlm.nih.gov/pubmed/34572943
http://dx.doi.org/10.3390/cancers13184716
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