# Compensatory Mechanisms that Promote Homologous Recombination in BRCA1 Mutant Cancers

> **NIH NIH R01** · RESEARCH INST OF FOX CHASE CAN CTR · 2024 · $470,000

## Abstract

PROJECT SUMMARY
A frequent mode of therapy resistance is through the restoration of homologous recombination (HR) DNA repair,
which can occur via secondary reversion mutations, or loss of DNA end resection proteins. While reversion
events are commonly detected, mutations in DNA end resection proteins are less frequently reported in patients,
and the molecular drivers of clinical resistance in many BRCA1 cancers remain unknown. In this proposal, we
have identified genes that when mutated do not impact resection, but restore PALB2 recruitment and induce
PARPi resistance. We now hypothesize that PARPi resistance can occur when mutations occur in genes that
function to block PALB2 recruitment to sites of DNA damage. However, mechanistic details remain to be defined.
The rationale for the proposed research is that PALB2 inhibitory proteins play a role in regulating mammalian
DNA repair, and loss of function events may account for a significant portion of PARPi resistant patient cancers
where RAD51 activity is restored, but mutations in DNA end resection genes or BRCA1 reversion mutations are
not detected. We will validate these resistance pathways in relevant mouse models of BRCA1 mutant cancer.
We will address the following Specific Aims: 1) define molecular features of PALB2 required for HR.; 2) elucidate
mechanisms of PALB2 inhibition; and 3) examine the role of PALB2 regulators in PARPi resistance. Collectively,
these studies have the potential to reveal new paradigms for DNA repair pathway choice and therapy response
and resistance.

## Key facts

- **NIH application ID:** 10978813
- **Project number:** 2R01CA214799-06A1
- **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:** 2024
- **Award amount:** $470,000
- **Award type:** 2
- **Project period:** 2017-09-12 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978813

## Citation

> US National Institutes of Health, RePORTER application 10978813, Compensatory Mechanisms that Promote Homologous Recombination in BRCA1 Mutant Cancers (2R01CA214799-06A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10978813. Licensed CC0.

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