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Review

Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

by 1,2 and 1,2,*
1
Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
2
Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Dik C. van Gent
Cancers 2021, 13(18), 4716; https://doi.org/10.3390/cancers13184716
Received: 6 August 2021 / Revised: 10 September 2021 / Accepted: 16 September 2021 / Published: 21 September 2021
(This article belongs to the Special Issue Prognostic and Predictive Markers in Pancreatic Cancer)
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.
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. View Full-Text
Keywords: homologous recombination deficiency; pancreatic cancer; DNA damage repair homologous recombination deficiency; pancreatic cancer; DNA damage repair
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MDPI and ACS Style

Wattenberg, M.M.; Reiss, K.A. Determinants of Homologous Recombination Deficiency in Pancreatic Cancer. Cancers 2021, 13, 4716. https://doi.org/10.3390/cancers13184716

AMA Style

Wattenberg MM, Reiss KA. Determinants of Homologous Recombination Deficiency in Pancreatic Cancer. Cancers. 2021; 13(18):4716. https://doi.org/10.3390/cancers13184716

Chicago/Turabian Style

Wattenberg, Max M., and Kim A. Reiss 2021. "Determinants of Homologous Recombination Deficiency in Pancreatic Cancer" Cancers 13, no. 18: 4716. https://doi.org/10.3390/cancers13184716

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