This effect is caused by the combination of PARP inhibitor-induced DNA double-strand break (DSB) formation and functional deficiency of homologous recombination (HR) repair, which is the main repair pathway for DNA damage. On the other hand, the clonal evolution in tumors as a tumor ...
Alterations in the target of PARPi that reduce binding to PARP1 or alter the function of PARP1 have been uncovered as a mechanism of resistance. PARP inhibition impairs DNA replication by generating PARP-DNA adducts; however, downregulation of PARP1 or alterations in the DNA-binding domains of ...
H. Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Proc. Natl Acad. Sci. USA 108, 3406–3411 (2011). CAS PubMed PubMed Central Google Scholar Zahradka, P. & Ebisuzaki, K. A shuttle mechanism for DNA-...
Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials. Cancer Letters 2017; 386: 47-56 【14】Hopkins TA, Shi Y, Rodriguez LE, et al. Mechanistic Dissection of PARP1 Trapping and the Impact on In Vivo Tolerability and ...
PARP: Mechanism of action PARP is a family of 17 intracellular enzymes associated with the cellular stress response, chromatin remodeling, DNA repair, and apoptosis [165]. In general, PARPs mediate reversible posttranslational modification via synthesis of nucleic acid mimic molecules known as poly-AD...
This review mainly introduces the concept of synthetic lethality and homologous recombination, describes the mechanism of action of PARP inhibitors within this concept, discusses problems such as resistance, enumerates the current progress and achievements of clinical trials for PARP inhibitors in pancreatic...
Although several of these drugs have been shown to inhibit PARP in vivo, their spectrum of activity and effects on DNA repair pathways make them distinct. This review summarizes current insights into the mechanism of action, recent clinical trials, and potential next steps in the evaluation of ...
PARP trapping represents an additional mechanism of action for PARPi, and there are preclinical data to suggest that the consequences of trapped PARP–DNA complexes are actually more cytotoxic than the unrepaired SSBs that initially result from the loss of PARP activity [20]. Though preclinical ...
Although several of these drugs have been shown to inhibit PARP in vivo, their spectrum of activity and effects on DNA repair pathways make them distinct. This review summarizes current insights into the mechanism of action, recent clinical trials, and potential next steps in the evaluation of ...
In their initial studies, Pommier and his colleagues found that the PARP inhibitor olaparib was more toxic tocultured cellsthan genetic elimination of PARP1. According to Pommier, these results indicated that olaparib must have additional modes of action, and their detailed cellular analyses identified...