Synthetic lethality strategies for cancer therapy exploit cancer-specific genetic defects to identify targets that are uniquely essential to the survival of tumor cells. Here we show RAD27/FEN1, which encodes flap endonuclease 1 (FEN1), a structure-specific nuclease with roles in DNA replication and repair, and has the greatest number of synthetic lethal interactions with Saccharomyces cerevisiae genome instability genes, is a druggable target for an inhibitor-based approach to kill cancers with defects in homologous recombination (HR). The vulnerability of cancers with HR defects to FEN1 loss was validated by studies showing that small-molecule FEN1 inhibitors and FEN1 small interfering RNAs (siRNAs) selectively killed BRCA1- and BRCA2-defective human cell lines. Furthermore, the differential sensitivity to FEN1 inhibition was recapitulated in mice, where a small-molecule FEN1 inhibitor reduced the growth of tumors established from drug-sensitive but not drug-resistant cancer cell lines. FEN1 inhibition induced a DNA damage response in both sensitive and resistant cell lines; however, sensitive cell lines were unable to recover and replicate DNA even when the inhibitor was removed. Although FEN1 inhibition activated caspase to higher levels in sensitive cells, this apoptotic response occurred in p53-defective cells and cell killing was not blocked by a pan-caspase inhibitor. These results suggest that FEN1 inhibitors have the potential for therapeutically targeting HR-defective cancers such as those resulting from BRCA1 and BRCA2 mutations, and other genetic defects.

癌症治疗的合成致死性策略利用了癌症特有的遗传缺陷来鉴定对于肿瘤细胞的生存至关重要的靶标。在这里，我们显示RAD27 / FEN1，它编码襟翼内切核酸酶1（FEN1），这是一种结构特异性核酸酶，在DNA复制和修复中起作用，并且与啤酒酵母基因组不稳定性基因具有最大的合成致死相互作用，是药物的靶点一种基于抑制剂的方法来杀死同源重组（HR）缺陷的癌症。与HR缺陷FEN1损失癌症的漏洞由研究表明，小分子抑制剂FEN1和FEN1小干扰RNA（siRNA）选择性地杀死验证BRCA1 -和BRCA2缺陷的人类细胞系。此外，在小鼠中概括了对FEN1抑制的不同敏感性，其中小分子FEN1抑制剂减少了由药物敏感但对药物没有耐药性的癌细胞系建立的肿瘤的生长。FEN1抑制在敏感和耐药细胞系中均诱导DNA损伤反应。然而，即使去除了抑制剂，敏感的细胞系也无法恢复和复制DNA。尽管FEN1抑制可在敏感细胞中激活caspase较高的水平，但这种凋亡反应发生在p53缺陷细胞中，而泛半胱天冬酶抑制剂并未阻止细胞杀伤。这些结果表明，FEN1抑制剂具有治疗靶向HR缺陷性癌症的潜力，例如BRCA1和BRCA2突变和其他遗传缺陷。