# Assessing DNA polymerase theta as a therapeutic target in BRCA1 mutant cancer

> **NIH NIH R01** · RESEARCH INST OF FOX CHASE CAN CTR · 2022 · $430,050

## Abstract

PROJECT SUMMARY
Genetic disruption of DNA polymerase theta (Polθ) activity has been shown to effectively target BRCA1 mutated
cells, while leaving BRCA1 wild-type (WT) cells intact. Polθ facilitates theta-mediated DNA end joining (TMEJ)
repair by promoting DNA synapsis and repair synthesis at break sites containing 3' single stranded (ss)DNA
overhangs. Although small molecule inhibitors of Polθ activity are currently under development for the treatment
of BRCA1 mutant cancers, very little is known regarding the mechanisms that activate TMEJ and result in Polθ-
dependency in BRCA1 mutant cells. Moreover, the current paradigm assumes that homologous recombination
(HR)-deficiency confers Polθi sensitivity, therefore PARPi responsiveness is expected to be a biomarker for Polθ
inhibitor (Polθi) sensitivity. In our preliminary data, we unexpectedly identified commonly used Brca1 mutant
cells that grow relatively unperturbed with genetic Polq (Polθ) knockout (KO), indicating that Polθi and PARPi
sensitivity may not necessarily correlate. In this proposal, we will elucidate the molecular requirements for TMEJ
activation and identify biological factors that distinguish PARPi and Polθi sensitivity. We will address the following
Specific Aims: 1) reveal the molecular basis of TMEJ activation in Brca1 mutant cells; 2) uncover genetic Polθ-
dependencies in Brca1 mutant cells; and 3) examine pharmacologic Polθ inhibition in Brca1 mutant cells.
Collectively, these studies will be informative for future clinical studies employing Polθi.

## Key facts

- **NIH application ID:** 10446399
- **Project number:** 1R01CA262466-01A1
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** Neil Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $430,050
- **Award type:** 1
- **Project period:** 2022-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446399

## Citation

> US National Institutes of Health, RePORTER application 10446399, Assessing DNA polymerase theta as a therapeutic target in BRCA1 mutant cancer (1R01CA262466-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10446399. Licensed CC0.

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