# Implications of the ATR Checkpoint Kinase in Radiation and Targeted Therapies

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $391,954

## Abstract

Summary
ATR is a master regulator of the DNA damage response in human cells. Inhibition of ATR
sensitizes cancer cells to radiation and DNA-damaging drugs, providing an attractive strategy to
improve radiotherapy and chemotherapy. Furthermore, in cancer cells with significant intrinsic
genomic instability, inhibition of ATR results in massive DNA damage, thereby killing cancer cells
by exploiting the vulnerability of their own genomes. Identification of the intrinsic liabilities of
cancer cells that render them reliant on ATR for survival will greatly facilitate the use of ATR
inhibitors in targeted therapy and radiotherapy. Several ATR inhibitors are already on clinical trials
and showing promising efficacy. However, despite the success of initial trials, it is still largely
unknown whether and how ATR inhibitors can be broadly used to target different types of genomic
vulnerabilities of cancer cells. Recent studies suggested that R loops, a group of transcription
intermediates containing DNA:RNA hybrids and displaced single-stranded DNA, are a source of
genomic instability in cancer cells. In the preliminary studies leading to this application, we find
that ATR is activated by R loops and it plays a key role in suppressing R loop-associated DNA
damage. Furthermore, we show that cancer-associated RNA splicing factor mutations promote R
loop formation and render cells sensitive to ATR inhibition. These exciting findings lead us to
hypothesize that aberrant R loop accumulation is a new targetable liability of cancer cells.
Furthermore, ATR is a key sensor of R loops and a critical suppressor of R loop-associated DNA
damage, making ATR inhibition an attractive way to target the R-loop liability of cancer cells. To
these hypotheses, in Aim 1, we will elucidate the mechanisms by which ATR is activated by R
loops through a previously unknown pathway. In Aim 2, we will determine how ATR protects the
genome against R loops through three novel mechanisms. In Aim 3, we will test whether ATR
inhibitors can selectively eliminate cancer cells harboring high levels of R loops in vitro and in
vivo, and identify markers to predict the R-loop liability of tumors. In addition, we will investigate
whether radiation can be used to induce R loops in cancer cells and sensitize R loop-high tumors
to ATR inhibitors. Together, these studies will mechanistically explain how R loops are sensed by
ATR in cells, reveal how ATR enables cells to cope with R loop-associated genomic instability,
and address whether the R-loop liability of cancer cells can be effectively exploited by ATR
inhibitors in therapy. These studies will not only significantly advance our understanding of the
fundamental biology of R loops and ATR signaling, but also transform the use of ATR inhibitors
in targeted therapy and radiotherapy.

## Key facts

- **NIH application ID:** 9973670
- **Project number:** 2R01CA197779-06
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Lee Zou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $391,954
- **Award type:** 2
- **Project period:** 2015-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973670

## Citation

> US National Institutes of Health, RePORTER application 9973670, Implications of the ATR Checkpoint Kinase in Radiation and Targeted Therapies (2R01CA197779-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9973670. Licensed CC0.

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