Abstract
Due to the DNA repair defect, BRCA1/2 deficient tumor cells are more sensitive to PARP inhibitors (PARPi) through the mechanism of synthetic lethality. At present, several PAPRi targeting poly (ADP-ribose) polymerase (PARP) have been approved for ovarian cancer and breast cancer indications. However, PARPi resistance is ubiquitous in clinic. More than 40% BRCA1/2-deficient patients fail to respond to PARPi. In addition, lots of patients acquire PARPi resistance with prolonged oral administration of PARPi. Homologous recombination repair deficient (HRD), as an essential prerequisite of synthetic lethality, plays a vital role in killing tumor cells. Therefore, Homologous recombination repair restoration (HRR) becomes the predominant reason of PARPi resistance. Recently, it was reported that DNA replication fork protection also contributed to PARPi resistance in BRCA1/2-deficient cells and patients. Moreover, various factors, such as reversion mutations, epigenetic modification, restoration of ADP-ribosylation (PARylation) and pharmacological alteration lead to PARPi resistance as well. In this review, we reviewed the underlying mechanisms of PARP inhibitor resistance in detail and summarized the potential strategies to overcome PARPi resistance and increase PARPi sensitivity.
Highlights
DNA damage response (DDR) is vital to maintaining genome stability [1]
When cells suffer from DNA damage, DDR is instigated and it can remove the damage by specified DNA repair pathways, including homologous recombination repair (HR), non-homologous end joining repair (NHEJ), single stranded break repair (SSBR) [2]
In the past few decades, Poly (ADP-ribose) polymerases (PARPs) inhibitor (PARPi) was successfully developed in treating BRCA mutation patients, which provided proof-of concept that synthetic lethal interactions could be translated into cancer therapy
Summary
DNA damage response (DDR) is vital to maintaining genome stability [1]. When cells suffer from DNA damage, DDR is instigated and it can remove the damage by specified DNA repair pathways, including homologous recombination repair (HR), non-homologous end joining repair (NHEJ), single stranded break repair (SSBR) [2]. In the G1 phase, 53BP1 and RIF1 proteins localize to DSB sites, leading to the inhibition of BRCA1 recruitment, blocking DNA resection and promoting NHEJ repair pathway. It has been suggested that the loss of 53BP1 induced DNA end resection and HR restoration, leading to PARPi resistance in various cancers, such as breast cancer [42], glioblastoma [46] and ovarian cancer [47].
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