Olaparib-Induced Senescence Is Bypassed through G2-M Checkpoint Override in Olaparib-Resistant Prostate Cancer

PARP inhibition represents the dawn of precision medicine for treating prostate cancer. Despite this advance, questions remain regarding the use of PARP inhibitors (PARPi) for the treatment of this disease, including (i) how specifically do PARPi-sensitive tumor cells respond to treatment, and (ii) how does PARPi resistance develop? To address these questions, we characterized response to olaparib in sensitive LNCaP and C4-2B cells and developed two olaparib-resistant derivative cell line models from each, termed LN-OlapR and 2B-OlapR, respectively. OlapR cells possess distinct morphology from parental cells and display robust resistance to olaparib and other clinically relevant PARPis, including rucaparib, niraparib, and talazoparib. In LNCaP and C4-2B cells, we found that olaparib induces massive DNA damage, leading to activation of the G(2)-M checkpoint, activation of p53, and cell-cycle arrest. Furthermore, our data suggest that G(2)-M checkpoint activation leads to both cell death and senescence associated with p21 activity. In contrast, both LN-OlapR and 2B-OlapR cells do not arrest at G(2)-M and display a markedly blunted response to olaparib treatment. Interestingly, both OlapR cell lines harbor increased DNA damage relative to parental cells, suggesting that OlapR cells accumulate and manage persistent DNA damage during acquisition of resistance, likely through augmenting DNA repair capacity. Further impairing DNA repair through CDK1 inhibition enhances DNA damage, induces cell death, and sensitizes OlapR cells to olaparib treatment. Our data together further our understanding of PARPi treatment and provide a cellular platform system for the study of response and resistance to PARP inhibition.

Automated summary

PARP inhibition represents the dawn of precision medicine for treating prostate cancer. This study investigates how PARP inhibitor-sensitive tumor cells respond to treatment and how resistance to PARP inhibitors develops. The research team characterized the response to olaparib in sensitive cells and developed olaparib-resistant cells to study resistance mechanisms. They found that olaparib induces DNA damage, activates the G(2)-M checkpoint, and leads to cell-cycle arrest in sensitive cells. In contrast, olaparib-resistant cells do not arrest at G(2)-M and display a blunted response to olaparib treatment. The study provides insights into PARP inhibitor treatment and offers a cellular platform system for studying response and resistance to PARP inhibition.