Therapeutic Potential of PARP Inhibitors in the Treatment of Gastrointestinal Cancers
Open accessAbstract
Gastrointestinal (GI) malignancies are a major global health burden, with high mortality rates. The identification of novel therapeutic strategies is crucial to improve treatment and survival of patients. The poly (ADP-ribose) polymerase (PARP) enzymes involved in the DNA damage response (DDR) play major roles in the development, progression and treatment response of cancer, with PARP inhibitors (PARPi) currently used in the clinic for breast, ovarian, fallopian, primary peritoneal, pancreatic and prostate cancers with deficiencies in homologous recombination (HR) DNA repair. This article examines the current evidence for the role of the DDR PARP enzymes (PARP1, 2, 3 and 4) in the development, progression and treatment response of GI cancers. Furthermore, we discuss the role of HR status as a predictive biomarker of PARPi efficacy in GI cancer patients and examine the pre-clinical and clinical evidence for PARPi and cytotoxic therapy combination strategies in GI cancer. We also include an analysis of the genomic and transcriptomic landscape of the DDR PARP genes and key HR genes (BRCA1, BRCA2, ATM, RAD51, MRE11, PALB2) in GI patient tumours (n = 1744) using publicly available datasets to identify patients that may benefit from PARPi therapeutic approaches.
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PARP inhibitors have also shown efficacy when used in combination with DNA-damaging agents such as chemotherapy and radiotherapy.
“Additionally, PARP inhibitors have also shown efficacy when used in combination with DNA-damaging agents such as chemotherapy and radiotherapy [50,134].”
From Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer (2025) · cites this paper as [134]
Section 7.1 reports improved tumour-cell responses when PARP inhibitors were combined with chemotherapy or radiation in preclinical studies. Section 7.2 describes promising early-phase clinical results but says later-phase success is still needed; some trials found no benefit. The unqualified statement that these combinations have shown efficacy overstates the clinical evidence in this review. (LLM, conf=0.84)
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References 186 · Cited by 24
Research works printed but not linked: 2
- [76]Longnecker D.S. Pathology of Exocrine Pancreatic Neoplasms UpToDate Clinical Summaries 35th ed. Goldberg R.M. Wolters Kluwer Philadelphia, PA, USA 2020
- [142]Miknyoczki S.J. Jones-Bolin S. Pritchard S. Hunter K. Zhao H. Wan W. Ator M. Bihovsky R. Hudkins R. Chatterjee S. Chemopotentiation of Temozolomide, Irinotecan, and Cisplatin Activity by CEP-6800, a Poly(ADP-Ribose) Polymerase Inhibitor Mol. Cancer Ther. 2003 2 371 12700281
- Authors
- Alhusaini, A., Cannon, A., Maher, S. G., Reynolds, J. V., & Lynam-Lennon, N.
- Affiliations
- St. James's Hospital (IE)
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, St. James’s Hospital, D08 W9RT Dublin 8, Ireland
- Venue
- Biomedicines
- Publisher
- MDPI AG
- Published
- 2021-08-16
- Volume
- 9
- Issue
- 8
- Pages
- 1024
- ISSN
- 2227-9059 (ISSN-L)
- PMC
- PMC8392860
- OpenAlex
- W3195238703
- Cited by
- 24
- References
- 186
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 7 · 2022: 2 · 2021: 1
- FWCI
- 0.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Biomedicines (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Health Research Board (ILP-POR-2017-007, EIA-2017-020)
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- PARP inhibitors, gastrointestinal cancer, DNA damage response, homologous recombination deficiency, PARP1, PARP2, PARP3, PARP4, predictive biomarkers, BRCA1, BRCA2, ATM, RAD51, MRE11, PALB2, gene expression profiling
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