# NAD+ metabolism in PARP inhibitor resistance of ovarian cancer

> **NIH NIH R37** · MAYO CLINIC ROCHESTER · 2022 · $363,713

## Abstract

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.

## Key facts

- **NIH application ID:** 10430256
- **Project number:** 5R37CA261854-02
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Arun Kanakkanthara
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $363,713
- **Award type:** 5
- **Project period:** 2021-06-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10430256

## Citation

> US National Institutes of Health, RePORTER application 10430256, NAD+ metabolism in PARP inhibitor resistance of ovarian cancer (5R37CA261854-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10430256. Licensed CC0.

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