UC San Diego

Synthetic lethal strategies for cancer therapeutics seek to target genetic defects or vulnerabilities in tumor cells, while sparing normal cells. Here we identified that RAD27/ FEN1, which encodes Flap Endonuclease 1, has the greatest number of synthetic lethal interactions with Saccharomyces cerevisiae genome instability genes and is thus a potential target for an inhibitor-based approach to kill cancer cells with genome instability. FEN1 inhibition specifically targeted BRCA1- or BRCA2-defective members of matched pairs of human cell lines, and BRCA-deficient cancer cell lines tended to show increased sensitivity to FEN1 inhibition or knockdown, regardless of their olaparib sensitivity. Both sensitive and resistant cell lines showed increased DNA damage responses upon FEN1 inhibition; however, sensitive cell lines were unable to recover and replicate DNA even when the drug was removed. Although FEN1 inhibition can induce an apoptotic response, inhibition of apoptosis did not rescue sensitive cell lines. Rather, we found that FEN1 inhibition increased chromosome breaks in sensitive cells characteristic of mitotic catastrophe. These results suggest that FEN1 inhibitors are potentially valuable for targeting cancers with defects in homologous recombination and that cycles of drug treatment could be effective for killing sensitive cells.