Deadly synergy

Ludwig San Diego’s Richard Kolodner and colleagues reported in the Proceedings of the National Academy of Sciences in July a “synthetic lethal” interaction that might be exploited for therapy in cancers with mutations in their BRCA1 and 2 genes, which are implicated in breast, ovarian and other cancers. Synthetic lethality occurs when the mutation of two genes—neither of which is on its own vital to cell survival—causes cell death. Building from their studies on yeast cells, Richard’s team discovered that disabling or removing FEN1, a mammalian gene that is important for DNA replication and repair, is deadly to cancer cells with BRCA mutations. Similarly, a drug-like FEN1-blocking molecule they synthesized, C8, replicated the effects of FEN1 loss and proved to be an effective killer of such cells. The researchers then grafted C8-sensitive and C8-resistant tumors into mice and showed that C8 significantly inhibited the growth of the C8-sensitive tumors but not the C8-resistant tumors. Notably, not all the cancer cell lines and tumors that responded to C8 treatment were BRCA deficient, indicating that FEN1 has synthetic lethal interactions with other genes as well. These findings identify FEN1 as a novel target for drugs to treat a variety of malignancies.

This article appeared in the December 2020 issue of Ludwig Link. Click here to download a PDF (1 MB).


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