Background:
Poly-(ADP-Ribose) Polymerase (PARP) plays a central role in recovery
from single-strand DNA (ssDNA) damage via base excision repair. When PARP activity is
inhibited by a NAD+ mimetic analog, ssDNA is converted into a Double-Strand Break (DSB)
during the S-phase in a cell cycle. However, the DSB site is repaired in a process of Homologous
Recombination (HR) that is derived by genes such as BRCA1/2, PALB2, and RAD51. Under
conditions of HR dysfunction, including mutations of BRCA1/2 (called BRCAness), PARP
inhibitor (PARPi) induces “synthetic lethality” in BRCAness-specific cancer cells. Indeed, clinical
trials using forms of PARPi that include olaparib, veliparib and rucaparib, have revealed that
PARP inhibition produces a dramatic effect that actually arrests cancer progression. Its clinical
efficiency is limited, however, due to the acquisition of PARPi resistance during long-term use of
this inhibitor. Thus, it is important to elucidate the mechanisms of PARPi resistance.
Methods:
We searched the scientific literature published in PubMed, with a special focus on
kinase phosphorylation that is involved in acquiring PARPi resistance. We also summarized the
possible molecular events for recovering HR system, a key event for acquiring PARPi resistance.
Results:
CDK1 is a critical kinase for 5’-3’ DNA end resection, which is important for generating
ssDNA for recruiting HR-priming factors. CDK12 is necessary for the transcription of HR-driver
genes, such as BRCA1, BRCA2, RAD51 and ATR via the phosphorylation of RNA Pol-II. PLK-1
participates in driving HR via the phosphorylation of RAD51. The PI3K-AKT-mTOR signaling
cascade is involved in BRCA1 induction via an ETS1 transcriptional pathway. Even under ATMdeficient
conditions, the ATR-CHK1 axis compensates for loss in the DNA damage response,
which results in HR recovery. The HGF receptor Met tyrosine kinase is responsible for promoting
DNA repair by activating the PARP catalytic domain.
Conclusion:
These kinase-based signaling pathways are biologically important for understanding
the compensatory system of HR, whereas inactivation of these kinases has shown promise for the
release of PARPi resistance. Several lines of preclinical studies have demonstrated the potential
use of kinase inhibitors to enhance PARPi sensitivity. We emphasize the clinical importance of
chemical inhibitors as adjuvant drugs to block critical kinase activities and prevent the possible
PARPi resistance.
