October 24, 2013
Current cancer treatments are a lot like trying to destroy a particular red plate by letting a bull loose in a china shop. Yes, the plate is eventually smashed, but the collateral damage is pretty severe.
Ideally we would want something a bit more discriminating than an enraged bull. We might want an assassin that can fire a single bullet that destroys that red plate.
One way to identify the assassin that can selectively find and destroy cancer cells is by taking advantage of the idea of synthetic lethal mutations. “Synthetic lethal” is a genetic term that sounds a lot more complicated than it really is. Basically the idea is that mutating certain pairs of genes kills a cell, although mutating each gene by itself has little or no effect.
A synthetic lethal strategy seems tailor made for cancer treatments. After all, a big part of what happens when a cell becomes cancerous is that it undergoes a series of mutations. If scientists can find and target these mutated genes’ synthetically lethal partners, then the cancer cell will die but normal cells will not.
This is just what Deshpande and coworkers set out to do in a new study in the journal Cancer Research. They first scanned a previous screen that looked at 5.4 million pairwise interactions in the yeast S. cerevisiae to find the best synthetic lethal pairs. They found 116,000 pairs that significantly affected cell growth only if both genes in the pair were mutated.
A deeper look into the data revealed that 24,000 of these pairs had human orthologs for both genes. In 500 of these pairs, at least one of the partner genes had been shown to be mutated in certain cancers. Using a strict set of criteria (such as the strength and reproducibility of the synthetic lethal effect, and the presence of clear one-to-one orthology between yeast and human), the authors narrowed these 500 down to 21 pairs that they decided to study in mammalian cell lines.
When the authors knocked down the expression of both genes in these 21 gene pairs in a mammalian cell line, they found six that significantly affected growth. They focused the rest of the work on the strongest two pairs, SMARCB1/PMSA4 and ASPSCR1/PSMC2. These mammalian gene pairs correspond to the yeast orthologs SNF5/PRE9 and UBX4/RPT1, respectively.
The authors identified two separate cancer cell lines that harbored mutated versions of the SMARCB1 gene. When this gene’s synthetic lethal partner, PMSA4, was downregulated in these cancer lines, the growth of each cell line was severely compromised. The same was not true for a cell line that had a wild type version of SMARCB1—this cell line was not affected by downregulating PMSA4. The authors used a synthetic lethal screen in yeast to identify a new cancer target which when downregulated selectively killed the cancer without killing “normal” cells.
This proof of principle set of experiments shows how the humble yeast may one day speed up the process of finding cancer treatments without all those nasty side effects (like vomiting, hair loss, anemia and so on). Yeast screens can first be used to identify target genes and then perhaps also to find small molecules that affect the activity of those gene products. Yeast may one day tame the raging bull in a china shop that is current cancer treatments.
by D. Barry Starr, Ph.D., Director of Outreach Activities, Stanford Genetics