"Synthetic lethality" kills cancer by blocking DNA repair mechanism
“Synthetic lethality” is a phenomenon where genetic mutations that normally don’t harm a cell suddenly become deadly when paired up. Now, scientists have found a way to use this method to selectively kill off cancer that results from genetic mutations, without harming healthy cells.
The study focused on two particular genes called BRCA1 and BRCA2, that when mutated, boost a person’s chance to develop certain types of cancer. Specifically, these mutations are associated with a higher risk of breast and ovarian cancer in women, and breast and prostate cancer in men.
That means that these if certain synthetic lethal relationships are found in these mutations, activating them would kill only the cancer cell lines and not healthy cells. So for the new study, scientists from the University of California San Diego and the Ludwig Institute for Cancer Research explored these possibilities, studying a species of yeast called Saccharomyces cerevisiae.
One particular enzyme stood out – Flap Endonuclease 1 (FEN1) – due to its key role in DNA replication and repair. The researchers blocked FEN1 in human cell cultures, using either a drug inhibitor or genetically knocking it out, and in both cases found that it killed more of the BRCA1 and BRCA2 mutant cancer cell lines. Healthy cells, on the other hand, were found to recover from having FEN1 inhibited.
Next, the researchers tested the method in mice which had human cancers. Sure enough, blocking FEN1 in these animals also worked to reduce the growth of the tumors.
The team says that the study shows that FEN1 inhibitors could be a new avenue for future research to explore, as potential cancer therapies.
The research was published in the journal Proceedings of the National Academy of Sciences.