Poly adenosine diphosphate-ribosylation, a promising target for colorectal cancer treatment

The development of colorectal cancer(CRC)can result from changes in a variety of cellular systems within the tumor microenvironment.Particularly,it is primarily associated with genomic instability that is the gradual accumulation of genetic and epigenetic changes consisting of a characteristic set of mutations crucial for pathways in CRC progression.Based on this background,the potential to focus on poly[adenosine diphosphate(ADP)-ribose]polymerase(PARP)-1 and poly-ADP ribosylation(PARylation)as the main causes of malignant formation of CRC may be considered.One of the important functions of PARP-1 and PARylation is its deoxyribonucleic acid(DNA)repair function,which plays a pivotal role in the DNA damage response and prevention of DNA damage maintaining the redox homeostasis involved in the regulation of oxidation and superoxide.PARP-1 and PARylation can also alter epigenetic markers and chromatin structure involved in transcriptional regulation for the oncogenes or tumor suppressor genes by remodeling histone and chromatin enzymes.Given the high importance of these processes in CRC,it can be considered that PARP-1 and PARylation are at the forefront of the pathological changes required for CRC progression.Therefore,this review addresses the current molecular biological features for understanding the multifactorial function of PARP-1 and PARylation in CRC related to the aforementioned roles;furthermore,it presents a summary of recent approaches with PARP-1 inhibition in non-clinical and clinical studies targeting CRC.This understanding could help embrace the importance of targeting PARP-1 and PARylation in the treatment of CRC,which may present the potential to identify various research topics that can be challenged both nonclinically and clinically.

Mechanisms of resistance to PARP inhibitors - an evolving challenge in oncology

Poly-adenosine diphosphate ribose polymerase inhibitors(PARPi)lead to synthetic lethality when used in cancers harbouring a BRCA mutation or homologous recombination deficiency.There are now four PARPi approved by the Food and Drug Administration for therapeutic use is ovarian and breast cancer.In addition to this,there is data supporting its use in pancreatic adenocarcinoma and prostate cancer.However,development of resistance to PARPi limits the duration of response.Key mechanisms found to date include:(1)restoration of homologous recombination;(2)changes in PARP1;(3)suppression of non-homologous end joining;(4)replication fork protection;and(5)drug concentration.Gaining a better understanding of resistance mechanisms may guide combination therapies to overcome the resistance and improve the efficacy of PARPi.The purpose of this review is to describe the resistance mechanisms to PARPi and discuss their early detection.