Ludwig cancer research, has revealed a new instance in which simultaneous mutation of two nonessential genes;none of which are vital for the survival of cells can cause cancer cell death.
Headed by member of the Ludwig San Diego Richard Kolodner and published in the current The proceedings of the National Academy of Sciences, the study also shows that it is a deadly combination, or “synthetic lethality” can be reproduced in a drug-like molecule that can be used to treat cancer.
The development and FDA approval of a new generation of drugs called PARP inhibitors, for the treatment of malignant tumors with defects in tumor suppressor genes BRCA1 and BRCA2 that cause breast cancer, ovarian and many other cancers, have generated significant interest in using synthetic lethal interactions to develop cancer treatments.
Scientists, including group Kolodner, are on the hunt for other synthetic lethal interactions in cancers. “PARP inhibitors are a major step forward, but they are not perfect. Patients can become resistant to them, so there’s always a need for new and better treatments.”
Building from research done on yeast cells, Kolodner and his colleagues found that disabling or removing FEN1 gene of mammals, which is essential for DNA replication and repair, is fatal to cancer cells, mutated forms of the genes BRCA1 and 2.
We have provided information that should make people think FEN1 as a potential interesting therapeutic target and showed how yeast can be used to predict a number of synthetic lethal interactions, which can then be tested in a bona FIDE cancer cell lines with genetic instruments”.
Richard Kolodner, Professor, Professor, Department of cellular and molecular medicine, University of California, San Diego
In previous work with yeast Saccharomyces as a model to identify and study genes that maintain the integrity of the genome, Kolodner and his colleagues found that the RAD27 gene, and of synthetic lethal interactions with the 59 other nonessential genes of yeast.
Two such genes, it should be noted RAD51 and RAD52 play a role in recombination of DNA.
FEN1 is a close analogue or homologue, RAD27 in mammals. Based on their studies of yeast, Kolodner and his colleagues predicted that FEN1 synthetic lethal interactions with BRCA1 and BRCA2, which function in the same biochemical reactions in mammals, as RAD51 and RAD52 to do in yeast.
To test this hypothesis, they synthesized four FEN1-blocking molecules and used the best of them, S8, to suppress the activity of FEN1 in tumor cell lines with or without BRCA mutations. C8 proved to be an effective killer of BRCA-mutant cells.
Then they demonstrated that genetic disorders FEN1 expression had the same effect that S8 did for the breast cancer gene-mutant cells, confirming that the S8 worked, causing synthetic lethality.
Finally, the researchers instilled in C8-C8 sensitive and-resistant tumors in mice and showed that C8 significantly inhibited the growth of C8-sensitive tumors, but not in C8-resistant tumors.
Interestingly, not all cancer cell lines and tumors that responded to treatment C8 was deficient BRCA, K, indicating that FEN1 and synthetic lethal interactions with other genes as well.
These results reveal FEN1 as a novel target for drugs for the treatment of various malignant tumors by induction of synthetic lethality.
They also demonstrate that yeast-based screens provide a powerful tool to accelerate the discovery of synthetic lethal interactions for potential therapeutic value;it is an ongoing project in the laboratory Kolodner.