Twins aren’t as rare as you might think. In fact, every human harbors many of them — in our genes.
About two-thirds of human genes have their own doppelgänger, a duplicated copy that often shares overlapping functions within the cell. Cancer cells can take advantage of gene twins, relying on one to stay alive if its pair is lost. But now, scientists have developed a method to turn gene twins to their advantage when studying cancer and seeking new drug targets.
In work published today in the journal Cell Reports, Fred Hutchinson Cancer Research Center scientists describe an approach that allows them to knock out genes in tandem, which could help identify which gene pairs may play a role in cancer, and which could make for attractive therapeutic targets.
“This project grew out of the recognition that due to extensive gene duplication, we may not be detecting the function of those duplicated genes in typical CRISPR screens — or really any genetic assay where you only knock out one gene at a time,” said Hutch cancer geneticist Dr. Alice Berger, who led the work and holds the Innovators Network Endowed Chair.
Cancer cells exploit gene twins’ overlapping activities, relying on one gene twin to keep key cellular processes going after the first is lost. Researchers studying genes one at a time may miss a gene’s effects on cancer, not suspecting that its twin is pulling the strings in the background. It might lead them to dismiss a key cancer gene (and its therapeutic potential) — a misstep that Berger and her team hope their approach can help scientists avoid.
“We saw the potential for using [this phenomenon] to identify drug targets and other important cancer genes that had been missed,” she said.
Gene twins in cancer: a window of opportunity
There isn’t a single answer to why our DNA contains so many genetic doubles. In some cases, they may be playing a role so essential to survival that cells always need a backup. In others, gene duplicates start traveling along diverging evolutionary trajectories, retaining some overlapping activities, but also picking up critical new functions unique to each twin.
Berger and graduate student Phoebe Parrish recognized that finding the twins that have maintained critical functional overlap (called “paralogs” in scientific jargon) could have two different therapeutic uses.
“The first one is that we can just identify paralogs that are important for cancer that had been missed [before],” Berger said. “We might be able to target both paralogs with the same small molecule [drug] because they’re so much like each other.”
Some cancer drugs already work by blocking two paralogs with one therapeutic. Ibrance (palbociclib) and Kisquali (ribociclib), which have been approved for treatment of certain kinds of breast cancer, each inhibit both CDK4 and CDK6, enzymes that regulate cell proliferation. Perhaps the team could identify other pairs with the same co-druggable potential.
The other situation in which scientists could take advantage of gene twins is in the case of cancers that are forced to rely heavily on one gene twin after having lost the other. In theory, these cells would become extremely vulnerable to drugs that target the surviving twin.
“If you could have a specific inhibitor of one of those paralogs, then you could specifically target tumors that have lost the other paralog,” Berger explained. “Then you would have a therapeutic window in the tumor compared to the surrounding normal cells.”
