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Significance Analysis of synthetic lethal relationships identified inSaccharomyces cerevisiae was used to identify candidate therapeutic targets for cancers withBRCA1 orBRCA2 defects. Inhibition of one of these targets, flap endonuclease 1 (FEN1), with small-molecule inhibitors or siRNA knockdown of FEN1 expression preferentially killedBRCA1 andBRCA2 mutant cancer cell lines as well as some additional cancer cell lines withoutBRCA1 orBRCA2 defects. FEN1 inhibitors also preferentially reduced the growth of mouse xenografts established from FEN1 inhibitor-sensitive cancer cell lines. These studies support the use ofS. cerevisiae genetics in identifying human therapeutic targets and establish FEN1 as a potential therapeutic target for further investigation and possible development.

FEN1 endonuclease as a therapeutic target for human cancers with defects in homologous recombination