Abstract
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.
Highlights
Gastrointestinal (GI) malignancies are a major global burden, with an incidence of 4.9 million cases per year, and account for 32% of cancer-related mortality worldwide [1]
The four DNA damage response (DDR) poly (ADP-ribose) polymerase (PARP) enzymes (PARP1, 2, 3 and 4) have been demonstrated to play various roles in the development and progression of GI cancers. This highlights a potential for the use of PARP inhibitors (PARPi) in GI cancers to improve prognosis
PARP enzymes in the repair of cytotoxic therapy-induced DNA damage suggests a role for
Summary
Gastrointestinal (GI) malignancies (oesophageal, gastric, hepatic, gallbladder, pancreatic and colorectal) are a major global burden, with an incidence of 4.9 million cases per year, and account for 32% of cancer-related mortality worldwide [1]. DNA damage in cancer cells, alterations in DDR play a prominent role in resistance to these therapies [14,15,16,17,18,19,20] This supports the targeting of the DDR to improve treatment and survival of cancer patients. Both PARP1 and PARP2 are considered sensors of DNA damage, and their binding to DNA in response to damage activates their enzymatic action This results in the poly (ADP-ribose)-ylation (PARylation), or addition of PAR chains, to their target. As the DDR PARP enzymes are involved in a wide variety of DNA damage repair pathways, their contribution to the genomic stability and, the survival of cancer cells, support their therapeutic targeting in cancer. Damaged DNA is repaired [32]
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