Mechanistic insights into the monotherapy and combination potential of FEN1 inhibition in cancer therapy

Flap endonuclease 1 (FEN1) is a structure-specific nuclease with critical functions in DNA replication and repair. FEN1 has been proposed as an anti-cancer drug target because of its synthetic lethal interaction with homologous recombination deficiency (HRD). However, the exploration of FEN1 in this context has been hampered by the lack of suitable small molecule tools. Here, we describe MSC778, a highly potent, specific and selective small molecule inhibitor of FEN1 nuclease activity. MSC778 directly engages FEN1 in cells, enhances its retention on chromatin, and selectively kills BRCA-deficient cells. Mechanistically, MSC778 suppresses DNA replication causing S-phase accumulation, DNA damage, and ultimately, cell death. Cancer cell panel screening identified Ewing sarcoma (EWS) cells as sensitive to MSC778, which is driven by the expression of SLFN11. In addition to HRD, CRISPR screening revealed a spectrum of synthetic lethal interactions between MSC778 and DNA damage response (DDR) factors, such as PARP1, USP1, PARG, and ATR. Furthermore, we demonstrate that combined inhibition of these factors with MSC778 induces synergistic killing of cancer cells. Together these data highlight FEN1 inhibition as an attractive precision oncology strategy either as monotherapy or as a combination therapy with a broad range of current and next generation DDR-targeting agents.

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Publication Details

Journal
Nucleic Acids Research
Published
2025-10-29
DOI
https://doi.org/10.1093/nar/gkaf1279
Primary Topic
DNA Repair Mechanisms
Type
article
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0.00
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article

Mechanistic insights into the monotherapy and combination potential of FEN1 inhibition in cancer therapy

Claire McWhirter, Helen M.R. Robinson, Frank T. Zenke, Ulrich Pehl et al.
Nucleic Acids Research
DNA Repair Mechanisms
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Mechanistic insights into the monotherapy and combination potential of FEN1 inhibition in cancer therapy

Claire McWhirter, Helen M.R. Robinson, Frank T. Zenke, Ulrich Pehl, Julian Kreis, David Perera, Sam E. Mann, Silvia Peripolli, Julien Lefranc, Timothea Konstantinou, Maria Filipa Pinto, Elias Elinati, Ana Toste Rêgo, Lars T. Burgdorf, Bethany Mason, Eeson Rajendra, Balca R. Mardin, Ada Sala-Hojman, Lucy Armstrong, Alessandro Galbiati, Joerg Bomke, Robert A. Heald, Owen A. Davis, Birgitta Leuthner, Graeme C.M. Smith, Claudio A. Lademann, Stefanie Scharrelmann
article en

Abstract

Flap endonuclease 1 (FEN1) is a structure-specific nuclease with critical functions in DNA replication and repair. FEN1 has been proposed as an anti-cancer drug target because of its synthetic lethal interaction with homologous recombination deficiency (HRD). However, the exploration of FEN1 in this context has been hampered by the lack of suitable small molecule tools. Here, we describe MSC778, a highly potent, specific and selective small molecule inhibitor of FEN1 nuclease activity. MSC778 directly engages FEN1 in cells, enhances its retention on chromatin, and selectively kills BRCA-deficient cells. Mechanistically, MSC778 suppresses DNA replication causing S-phase accumulation, DNA damage, and ultimately, cell death. Cancer cell panel screening identified Ewing sarcoma (EWS) cells as sensitive to MSC778, which is driven by the expression of SLFN11. In addition to HRD, CRISPR screening revealed a spectrum of synthetic lethal interactions between MSC778 and DNA damage response (DDR) factors, such as PARP1, USP1, PARG, and ATR. Furthermore, we demonstrate that combined inhibition of these factors with MSC778 induces synergistic killing of cancer cells. Together these data highlight FEN1 inhibition as an attractive precision oncology strategy either as monotherapy or as a combination therapy with a broad range of current and next generation DDR-targeting agents.

Nucleic Acids ResearchVol. 53(22)
Babraham Institute (GB), Merck KGaA, Darmstadt (Germany) (DE), Babraham Bioscience Technologies (United Kingdom) (GB)
Openalex Percentile: Top 64%
DNA Repair Mechanisms
DOIOpen Access PDFOpenAlex
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