# FEN1 Endonuclease as a Synthetic Lethal Target for Cancer Therapy

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $626,700

## Abstract

PROJECT SUMMARY
Gross chromosomal rearrangements (GCRs), a type of genome instability, are often seen in inherited and
sporadic cancers and are an important driver of malignant progression. For example, hereditary breast and
ovarian cancers resulting from BRCA1 and BRCA2 germline mutations suffer from homologous recombination
repair (HRR) defects that increase GCRs in model systems. Our previous studies have established a
comprehensive network of genome instability suppressor (GIS) genes in yeast and demonstrated in silico that
human homologs of these yeast GIS genes are genetically and/or epigenetically altered across many cancer
types. From yeast genetic studies, we have also identified and rank-ordered synthetic lethal (SL) partners of
non-essential GIS genes. The feasibility of targeting SL genetic interactions for rational cancer therapy has
been supported by the application of PARP inhibitors for maintenance therapy of breast and ovarian cancers
with BRCA1 or BRCA2 defects. To exploit additional SL interactions for cancer therapy, this proposal aims to
leverage the wealth of knowledge on GIS genes and their SL partners developed in yeast to guide the
development of therapeutics that target human GIS gene defects that cause GCRs in cancer. Specifically, the
proposed studies will focus on the human Flap Endonuclease 1 (FEN1), the homolog of yeast RAD27, which
has the highest number of SL-interactions with GIS genes of a variety of functions. FEN1 processes Okazaki
fragments during lagging strand DNA synthesis and acts in long-patch base excision repair but is itself non-
essential. To develop this nuclease as a target for treating cancers with defects in BRCA1, BRCA2 and other
FEN1-SL partner GIS genes, we propose to carry out the following lines of research: AIM 1) To expand
ongoing CRISPR-dropout screens and validation studies in cell lines and mice to (a) identify human genes in
which defects cause sensitivity to our proprietary FEN1-inhibitors of highly potency and specificity and (b)
define FEN1 SL-partner genes as well as cancer omics signatures that can be targeted with FEN1 inhibitors to
induce SL; AIM 2) To combine informatics and cell-based validation approaches for a deep-dive into cancer
omics and gene essentiality data to identify the spectrum and signatures of cancers amenable to therapeutic
targeting with FEN1 inhibitors; AIM 3) To apply an array of genetics-based approaches to investigate
mechanisms for acquired resistance to FEN1 inhibitors and to compare resistance to FEN1 versus PARP
inhibitors; and, AIM 4) To determine the effects of FEN1 inhibition on DNA replication, fork stability, and
chromosome integrity in BRCA1 and BRCA2 mutant cells to test the hypothesis that FEN1 inhibitors induce
irreparable damage to replication forks in HRR-deficient cancer cells to cause lethality. These mechanistic
studies will be extended to other validated FEN1-SL partner genes. These projects will greatly accelerate the
development of FEN...

## Key facts

- **NIH application ID:** 10675534
- **Project number:** 5R01CA255341-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Richard D Kolodner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $626,700
- **Award type:** 5
- **Project period:** 2021-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10675534

## Citation

> US National Institutes of Health, RePORTER application 10675534, FEN1 Endonuclease as a Synthetic Lethal Target for Cancer Therapy (5R01CA255341-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10675534. Licensed CC0.

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