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

Analysis of synthetic lethal relationships identified in Saccharomyces cerevisiae was used to identify candidate therapeutic targets for cancers with BRCA1 or BRCA2 defects. Inhibition of one of these targets, flap endonuclease 1 (FEN1), with small-molecule inhibitors or siRNA knockdown of FEN1 expression preferentially killed BRCA1 and BRCA2 mutant cancer cell lines as well as some additional cancer cell lines without BRCA1 or BRCA2 defects. FEN1 inhibitors also preferentially reduced the growth of mouse xenografts established from FEN1 inhibitor-sensitive cancer cell lines. These studies support the use of S. cerevisiae genetics in identifying human therapeutic targets and establish FEN1 as a potential therapeutic target for further investigation and possible development.