NAD+ metabolism in PARP inhibitor resistance of ovarian cancer

PROJECT SUMMARY/ABSTRACT High-grade serous ovarian cancer (HGSOC) remains the deadliest form of ovarian cancer, in part because most patients develop recurrent disease that is resistant to standard treatment, including platinum. Poly(ADP- ribose) polymerase (PARP) inhibitors (PARPis) have recently been approved as an important therapy for HGSOCs, especially for HGSOCs with defects in homologous recombination (HR) DNA repair due to mutations in BRCA1 or BRCA2. However, over 70% HGSOCs that initially respond to PARPis later develop resistant disease. Unfortunately, the underlying mechanisms of PARPi resistance are poorly understood. This project is designed to understand acquired PARPi resistance mechanisms and associated therapeutic vulnerabilities in HR-defective HGSOC. Our preliminary studies using HR-deficient HGSOC cell lines and patient derived xenograft (PDX) models show that acquired PARPi resistance is associated with high levels of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1). Our results also show that NMNAT1 upregulation results in an increase in NAD+ levels, which restores HR and creates a unique metabolic dependency in PARPi-resistant cells. These findings led to our central hypothesis that HR-deficient HGSOC acquire PARPi resistance by upregulating NMNAT1 that induces NAD+ levels leading to HR restoration as well as causing a metabolic dependency that may be therapeutically tractable. Guided by strong preliminary data, we propose three specific aims to: 1) examine how NMNAT1 is upregulated in HGSOC cells; 2) determine how NMNAT1 induces PARPi resistance; and 3) test whether NMNAT1-induced metabolic dependency in PARPi- resistant tumors can be targeted in preclinical models of HGSOC. These studies will unveil a previously unknown mechanism by which HGSOC cells become resistant to PARPis and may identify a potential new therapeutic option for PARPi-resistant HGSOC. The proposed work comprises an essential step toward our long-term goal of developing effective therapy for patients with HGSOC.