Ovcoming PARP Inhibitor Resistance

Abstract This proposal aims to investigate the mechanisms underlying PARP inhibitor (PARPi) resistance in prostate cancer and identify potential strategies to overcome this resistance. Prostate cancer is a prevalent cancer in men, and recently, PARPi has been approved to treat metastatic castrate- resistant prostate cancer (mCRPC) patients whose disease has stopped responding to second- generation anti-androgens and whose cancers are homologous recombination deficient (HRD). While some patients treated with PAPRi show promising results, a significant percentage of patients do not respond to these drugs even with HRD. In addition, acquired resistance inevitably develops. Thus, it is critical to identify mechanisms contributing to PARPi resistance. We have discovered that a specific isoform of histone methyltransferase NSD3, called NSD3S, is overexpressed in PARPi-resistant prostate cancer cells. Based on our preliminary data, we hypothesize that NSD3S plays a crucial role in driving PARPi resistance through its influence on replication fork dynamics. Furthermore, we have found that the NSD3S is regulated by a CRL E3 ubiquitin ligase whose misregulation contributes to NSD3S high expression in PARPi-resistant cells. We propose three specific aims to test these hypotheses. Aim 1 aims to investigate the mechanistic role of NSD3S in regulating DNA replication dynamics and its contribution to PARPi resistance. Aim 2 focuses on understanding the mechanisms responsible for NSD3S upregulation in PARPi-resistant lines. Aim 3 aims to explore new approaches based on our results to overcome PARPi resistance in prostate cancer using in vitro and in vivo models. Successful completion of this study would not only provide insights into the mechanisms of PARPi resistance and replication fork dynamics driven by NSD3S but also have implications for the development of precision medicine approaches in prostate cancer treatment.