TMIC-11. Study of PAX3 and PARP1 for genomic stability and drug resistance in glioblastoma

Abstract Cancer is a major threat to human health, with genomic instability being a primary cause of cancer, and replication stress serving as a crucial factor in genomic instability. Modern anticancer drugs often use the induction of high levels of replication stress in cancer cells to kill them. Therefore, understanding how cancer cells respond to replication stress is important. Studies have shown that PAX3 and PARP1 are highly expressed in glioma cells. We have preliminary discovered that PAX3, through PARP1, localizes to replication forks, reducing replication stress induced by anticancer drugs and contributing to drug resistance. Experiments have also revealed that PARP inhibitors (PARPi) prevent PAX3 from localizing to replication forks during replication, and PARPi are considered to have therapeutic potential. These results indicate that PARP1 plays an important role in PAX3’s ability to stabilize the genome under replication stress. Therefore, we hypothesize that PARP1 may recruit PAX3 to replication forks in glioma cells, reducing replication stress and promoting cancer cell survival. To confirm this hypothesis, we are collaborating with Taichung Veterans General Hospital (TVGH) to investigate the roles of PAX3 and PARP1 in regulating genomic stability and drug resistance in glioma cells. This study will analyze the relationship between PAX3 and PARP1 and the effects of PARP inhibitors on glioma cells. We expect that inhibiting PARP1 expression will affect PAX3’s ability to localize to replication forks, thereby impacting its function in suppressing replication stress, leading to increased genomic instability markers, and ultimately resulting in cancer cell death. The findings of this research will contribute to a deeper understanding of how glioma cells cope with replication stress to develop drug resistance and provide a theoretical basis for developing new therapeutic strategies based on PARP inhibitors.