# Understanding and targeting the DNA replication stress in cancer cells

> **NIH NIH R35** · DUKE UNIVERSITY · 2024 · $603,796

## Abstract

Project Summary
DNA replication problems collectively known as replication stress are a major sources of genomic instability in
cancer cells and also a vulnerability of cancer that can be targeted therapeutically. The recent success of PARP
inhibitors in the treatment of BRCA mutant tumors provided an exciting example of targeting cancer cells by
exploiting replication stress. However, our current understanding of the replication stress in cancer cells is still
very limited. Although we know that many different oncogenic events in cancer cells can cause replication
problems, we still don't fully understand whether these oncogenic events affect DNA replication in similar or
distinct ways. Furthermore, we also know little about how DNA replication is altered by different oncogenic
events, and whether altered replication can give rise to distinct cellular vulnerabilities. Understanding the basic
molecular features of replication stress, the major causes of replication stress in cancer cells, and the different
vulnerabilities resulting from altered replication will greatly enhance our ability to detect and exploit replication
stress in cancer therapy.
I have a longstanding interest in understanding the replication stress response in human cells. In particular, my
lab has extensively studied the functions and regulation of the ATR checkpoint pathway, the master regulator of
replication stress response in human cells. Our work has contributed significantly to the current models of stress
sensing and signaling during DNA replication. From recent studies by us and others, it has become gradually
clear that different oncogenic events in cancer cells can generate distinct problems in DNA replication.
Furthermore, RNA transcripts, the products of transcription, have both positive and negative impacts on DNA
replication and repair. Our studies also revealed that replication stress not only exerts cell autonomous effects
on the genome, but also cell non-autonomous effects in cell populations. Based on these new findings, we
propose to systematically define and characterize different types of replication stress in cancer cells, understand
how RNA affects replication and repair in the genome, and explore the cell non-autonomous effects of replication
stress in tumor microenvironments and cancer therapy. These studies may provide us a much more
comprehensive understanding of the molecular underpinnings of replication stress in cancer cells, their impacts
on the genome of cancer cells and cell populations in tumor microenvironments, and the cancer cell-specific
vulnerabilities that they give rise to. The new concepts and findings from these studies could have transformative
impacts on the research of cancer and cancer therapy.

## Key facts

- **NIH application ID:** 10652612
- **Project number:** 5R35CA263934-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Lee Zou
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $603,796
- **Award type:** 5
- **Project period:** 2023-03-24 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10652612

## Citation

> US National Institutes of Health, RePORTER application 10652612, Understanding and targeting the DNA replication stress in cancer cells (5R35CA263934-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10652612. Licensed CC0.

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