By Meghan Rosen
A new twist on a DNA-tweaking technology may help scientists hit cancer where it hurts.
Damaging tiny parts of cancer cells’ machinery can pinpoint potential Achilles’ heels, researchers suggest May 11 in Nature Biotechnology. These vulnerable spots may be good places to aim drugs, says study coauthor Christopher Vakoc, a molecular biologist at Cold Spring Harbor Laboratory in New York.
With the new method, “we can draw bull’s-eyes on what might be the best targets for drug development,” he says.
Designing drugs that harm cancer cells can be hit-or-miss. Even when researchers find the motors that drive a cancer’s growth, shutting them down with drugs is tricky. Some molecules will make the machinery grind to a halt; others won’t do anything. Because researchers can’t always predict which molecules will be winners, companies often waste time and money on drugs that just don’t work, Vakoc says. “This happens all the time in pharma.”
Vakoc and colleagues wanted to find out where cancer’s equipment was especially vulnerable — where throwing a monkey wrench would hurt the most. So the team fine-tuned a DNA-editing technology called the CRISPR/Cas9 system that other researchers have previously used to identify cancer cells’ survival equipment.
This equipment consists of proteins that help sustain cancer cell growth. Drugs that disable these proteins can cripple cancer cells, derailing the disease.
The CRISPR approach guides DNA-snipping molecular scissors to precise spots in the genome. Scientists can make the scissors chop up genes or even swap one gene for another. Vakoc’s team used the gene-editing tool to damage pieces of the DNA blueprints for cancer cells’ survival proteins. The scissors clipped away at nearly 1,000 different spots; the resulting DNA deviations altered tiny nooks and crannies in the cancer cells’ proteins. If any particular alteration made the cancer cells sick, the team could infer that that spot would be a good potential target for drugs to attack.
Testing this approach on cells in lab dishes, the researchers found six drug targets that had already been discovered for acute myeloid leukemia. The CRISPR strategy also identified 19 new potential targets.
“In one experiment, we’ve confirmed everything we’ve learned over the past decade,” Vakoc says. In the past, he says, just finding a single drug target took a lot of time, effort and intense experimentation. “Now,” he adds, “we can see everything, and it’s beautiful.”
The study highlights the power of CRISPR technology, says Ophir Shalem, an experimental and computational biologist at the Broad Institute in Cambridge, Mass. Vakoc’s new technique “increases the sensitivity of finding drug targets,” he says.
