Understanding DNA mutations is the backbone of cancer research, and many recent studies have focused on new ways to combat these mutations. A study published in Nature, led by members of the Cancer Dependency Map (DepMap) Project, found that the WRN gene is a molecular vulnerability shared by several cancer types, including colon, gastric, endometrial and ovarian.
Cells with a WRN dependency have a genetic feature called a microsatellite instability (MSI). This predisposition to mutation is only seen in cancer cells and is caused by a breakdown of one of the cell’s methods for repairing damaged DNA, called mismatch repair. Approximately 15% of colon cancers, 22% of gastric cancers, 20-30% of endometrial cancers and 12% of ovarian cancers diagnosed each year lack mismatch repair and possess MSI features.
About half of cancers with MSI features can be treated using checkpoint inhibitors. The DepMap research team focused on cancers that are unresponsive to checkpoint inhibitors to determine if the loss of mismatch repair activity that leads to MSI causes genetic dependencies in tumor cells. To study this phenomenon, researchers examined two genome-scale datasets: a CRISPR-Cas9 gene dataset from the DepMap project and an RNA set created by Project DRIVE.
There were 900 cancer cell lines in these datasets, 51 of which the researchers classified as MSI. Of these, the team found that 73% of the MSI lines depended on WRN. They also found that non-MSI cancer cell lines were relatively unaffected by WRN loss. When the team changed cells to turn off WRN expression, they discovered MSI cancers grew slower, but healthy cells were unaffected.
WRN creates a helicase, an enzyme that helps cells interpret DNA. No drugs currently exist to attack WRN, but it may soon become a target given the study’s results. Since the study showed that healthy, genetically stable cells can withstand the loss of WRN, drugs created to block the enzyme should impact cancer cells that are dependent on the enzyme without harming healthy cells. The loss of WRN can lead to Werner Syndrome, but researchers believe using medications for a short period of time should mitigate this risk.
“We’re hopeful that these findings will spark excitement among other academic and drug discovery teams, and that we can help push forward a treatment that will make a difference in patients,” co-senior author and DepMap associate director Francisca Vazquez said. “And more broadly, these findings illustrate how a cancer dependency map can help identify therapeutic targets and accelerate the development of precision cancer medicine.”