# Greatwall in replication stress/DNA damage responses and oral cancer resistance

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2021 · $363,375

## Abstract

Oral cancer, including cancers of the mouth and the back of the throat, is the sixth most common cancer
worldwide. In the United States, approximately 50,000 new oral cancer cases are diagnosed each year. First-
line treatments for oral cancer typically include surgery and radiation, with chemotherapy added to decrease
the possibility of metastasis, to eliminate residual tumor cells after surgery, to enhance the efficacy of radiation
(chemoradiation), and for patients with confirmed distant metastasis. Radiation and oral cancer
chemotherapeutics confer cytotoxicity largely by disrupting DNA replication to induce DNA damage.
Unfortunately, the prognosis of oral cancer, particularly HPV(-) cases, remains relatively poor, calling for a
better understanding of how cells respond to replication stress and DNA damage, and accordingly, developing
more effective treatment options and combinations to overcome drug resistance. In the current project, we
characterize a new role of Greatwall (Gwl) kinase in the replication stress and DNA damage responses. Gwl
was frequently upregulated in HPV(-) oral cancer, in correlation with cancer progression, tumor recurrence,
and poor patient survival. Gwl promoted the recovery and resistance of oral cancer cells to drugs that induce
replication stress and DNA damage. Gwl depletion or inhibition sensitized the drug responses in oral cancer
cells and mouse tumor models. Building on these findings, we hypothesize that Gwl mediates the cellular
responses to replication stress and DNA damage, and is therefore a potent target for oral cancer therapy. We
will uncover detailed mechanisms underlying the function and regulation of Gwl in the replication stress and
DNA damage responses; we will also establish the crucial proof-of-principle for the development of Gwl
targeting in cancer treatment. In Aim 1, we will delineate how Gwl is recruited to stalled replication forks via its
interaction with replication protein A (RPA) to regulate a phosphatase-mediated response to replication stress.
This study will shed new light on cancer progression and treatment, given that replication stress is a hallmark
of cancer, and that anti-replication drugs are commonly used in cancer therapy. In Aim 2, we will reveal a new
mechanism that leads to Gwl stabilization and accumulation after replication stress and DNA damage,
potentially as a key event that initiates cell recovery and confers tumor resistance. Upregulation of Gwl is
mediated directly by DNA damage signaling, suggesting a self-engaged “timer” mechanism that initiates cell
recovery and treatment resistance. Finally, guided by our mechanistic investigations, we will explore in Aim 3
therapeutic targeting of Gwl, using unique small molecule inhibitors which interfere with either Gwl kinase
activation or its interaction with RPA. Both patient-derived oral tumor xenograft and orthotopic syngeneic oral
tumor models will be utilized to comprehensively evaluate the therapeutic potential of ...

## Key facts

- **NIH application ID:** 10175963
- **Project number:** 1R01DE030427-01
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Aimin Peng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $363,375
- **Award type:** 1
- **Project period:** 2021-04-05 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10175963

## Citation

> US National Institutes of Health, RePORTER application 10175963, Greatwall in replication stress/DNA damage responses and oral cancer resistance (1R01DE030427-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10175963. Licensed CC0.

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