# Role of ALDH in PARP inhibitor resistance in HR-deficient ovarian cancer

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2022 · $340,189

## Abstract

Summary
 Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are an exciting and promising new class of
anticancer drugs, which have been approved by the FDA for recurrent ovarian cancer with BRCA1 or BRCA2
mutations, and as maintenance therapy after frontline therapy for platinum sensitive ovarian cancer regardless
of BRCA mutation. PARPi selectively kill BRCA1/2-deficient cancer cells through synthetic lethality. However,
patients receiving PARPi eventually develop cancer progression, and acquired PARP inhibitor resistance
remains a clinical hurdle. One of the mechanisms underlying acquired PARPi resistance is the restoration of
DNA repair capacity, mainly through the secondary mutations of BRCA1/2. Our preliminary study has
demonstrated that PARPi can enhance the Aldehyde dehydrogenase (ALDH) activity in ovarian cancer cells,
mainly through inducing expression of ALDH1A1, an isoform of the ALDH family. In addition, we also found that
ALDH1A1 is able to augment the microhomology-mediated end joining (MMEJ), one of the pathways for repairing
DNA double-strand breaks (DSBs), enhance the expression of DNA polymerase θ (Pol θ), a key player in the
MMEJ pathway, as well as reduce the sensitivity of BRCA2 mutated ovarian cancer cells to PARPi. Based on
this scientific premise, we generate a hypothesis that PARPi-induced overexpression of ALDH1A1 enhances
MMEJ via increasing the expression of Pol θ, and promotes cell survival after PARPi treatment in HR-deficient
cancer cells, eventually leading to acquired PARPi resistance. Consequently, inhibition of ALDH1A1 should be
able to synergize with PARPi in treating HR-deficient EOC, and reverse resistance to PARPi in HR-deficient
EOC. The main objective of this proposal is to determine a novel mechanism that contributes to PARPi
resistance in BRCA1/2-mutated EOC cells, and test the efficacy of targeting this mechanism in preventing and
reversing PARPi resistance in these cells. Two specific aims are proposed to test this hypothesis and achieve
our goal. In specific aim 1, we will determine the mechanism underlying PARPi-induced augmentation of MMEJ
in HR-deficient EOC cells and its contribution to PARPi resistance. In specific aim 2, we will determine the
therapeutic potential of an ALDH1A1 inhibitor, NCT-505, in preventing and reversing PARPi resistance in
BRCA1/2-mutated EOC in vitro and in vivo. It is our expectation that at the conclusion of this project, we will
have demonstrated a new mechanism contributing to the development of PARPi resistance in HR-deficient EOC.
We will have also shown the therapeutic potential of an ALDH1A1 inhibitor in treating these patients.

## Key facts

- **NIH application ID:** 10394792
- **Project number:** 5R01CA248027-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Qien Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $340,189
- **Award type:** 5
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10394792

## Citation

> US National Institutes of Health, RePORTER application 10394792, Role of ALDH in PARP inhibitor resistance in HR-deficient ovarian cancer (5R01CA248027-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10394792. Licensed CC0.

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