# Synthetic lethality based combination approaches to ARID1A mutation in ovarian cancer

> **NIH NIH R01** · WISTAR INSTITUTE · 2020 · $509,794

## Abstract

Project Summary
ARID1A, encoding a subunit of the SWI/SNF chromatin-remodeling complex, is the most frequently mutated
epigenetic regulator across human cancers. Most notably, inactivating mutations in ARID1A occur in ~50% of
ovarian clear cell carcinomas (OCCC) and ~30% of ovarian endometrioid carcinomas (OEC). There is an unmet
need for effective treatment modalities for ARID1A-mutated ovarian cancers. For example, OCCC is generally
refractory to standard agents used to treat epithelial ovarian cancer, and when diagnosed in advanced stages,
OCCC carries the worst prognosis of all ovarian cancer subtypes. The overall goal of this proposal is to develop
the first combinatorial targeted approach for ARID1A-mutated ovarian cancers with a durable outcome. We
show that the inhibition of EZH2 is synthetically lethal with ARID1A mutation. We also show that ARID1A
mutation is synthetically lethal with the inhibition of HDAC6. The objectives of this application are to
investigate mechanisms underlying this newly discovered synthetic lethality and to investigate a combination
therapeutic strategy for ARID1A-mutated ovarian cancer. Our central hypothesis is that targeting EZH2 and
HDAC6 using clinically applicable small molecule inhibitors can achieve a durable therapeutic outcome for
ARID1A-mutated ovarian cancer. Three Specific Aims are proposed: Aim 1 is to investigate the p53-dependent
mechanism by which ARID1A-mutated ovarian cancer cells are selectively sensitive to the inhibition of HDAC6;
Aim 2 will investigate the role of the SWI/SNF complex catalytic subunits switch in determining the sensitivity to
EZH2 inhibitors in ARID1A-mutated ovarian cancer cells; and Aim 3 will investigate the combinatorial therapeutic
strategy for ARID1A-mutated ovarian cancer by simultaneously inhibiting HDAC6 and EZH2. The proposed
studies are highly innovative because they challenge current research/clinical paradigms and utilize innovative
methods to explore new intervention strategies for ARID1A-mutated ovarian cancers. The research proposed
is of high impact because it has the potential to develop the first synthetic lethality-based, combinatorial
therapeutic strategy for ARID1A-mutated ovarian cancer with a durable outcome. Since ARID1A is the most
frequently mutated epigenetic regulator across human cancers, the mechanistic insights gained from the current
studies will have broad implications for many different types of cancers as well.

## Key facts

- **NIH application ID:** 9980335
- **Project number:** 5R01CA239128-02
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** Rugang Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $509,794
- **Award type:** 5
- **Project period:** 2019-07-18 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980335

## Citation

> US National Institutes of Health, RePORTER application 9980335, Synthetic lethality based combination approaches to ARID1A mutation in ovarian cancer (5R01CA239128-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9980335. Licensed CC0.

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