- Pancreatic cancer cells use the vitamin D receptor (VDR) to repair the damage caused by gemcitabine
- Treatments that inhibit VDR may render tumors more sensitive to cancer-killing drugs
- VDR appears to act epigenetically on RAD51 to fix DNA damage caused by chemotherapy and allow tumor cells to survive and continue dividing
Pancreatic cancer is one of the deadliest forms of the disease. Doctors’ typical line of attack involves DNA-damaging agents such as gemcitabine, but despite the potent activities of these drugs, patient survival is only extended by a few months, if that. Indeed, pancreatic cancer has the lowest five-year patient survival rate of any major form of cancer.
New research from Fox Chase has revealed one reason why: pancreatic cancer cells have an unlikely ally to help subvert the effects of chemotherapy.
That ally is the vitamin D receptor (VDR), typically associated with bone health. The findings by Fox Chase cancer biologist Timothy J. Yen, PhD, and colleagues point to a new way to potentially help chemotherapy do its job: disable VDR. “If we find a drug that inactivates VDR,” says Yen, who published the findings in the December 15 issue of Cell Cycle, “patients could manage their VDR deficiency by taking calcium supplements to make sure their bones and other tissues stay healthy.”
To uncover the role of VDR, Yen and his team used a genome-wide siRNA library to conduct a synthetic lethal screen in pancreatic tumor cells treated with a non-killing dose of gemcitabine. They identified 27 genes that when “knocked down” by the technology rendered cancer cells more vulnerable to the drug. Knocking out some genes, such as those associated with repairing DNA damage, was known to enhance gemcitabine’s effects. But one result made Yen and his colleagues scratch their heads.
When the researchers knocked out the gene for the receptor that binds vitamin D, cancer cells became as sensitive to gemcitabine as when they knocked out the known DNA repair genes. “In both cases, almost all of the cancer cells died,” says Yen.
“We suspect that cancer cells hijacked VDR and reassigned it to perform other cellular functions, such as repairing DNA damage caused by gemcitabine so the cancer can continue to divide and spread.” The findings were a big surprise, he says, since VDR had not shown to be either a tumor suppressor or oncogene, nor play a role in drug sensitization. “There was little information known about our findings so we had to tread carefully as this was uncharted territory.”
Although it’s not quite clear how VDR helps cancer cells sidestep gemcitabine, a key player appears to be RAD51. When the researchers knock out VDR, the RAD51 protein can’t function properly to help repair the damaged DNA. VDR appears to affect RAD51 at the epigenetic level, regulating chromosome structure by modifying the histone proteins that package the DNA. Indeed, when they added a drug that elevates levels of histone acetylation in cells lacking VDR, RAD51 function was restored.
These findings present both good news and bad news, says Yen. The good news is that VDR is a druggable target that binds to small molecules such as vitamin D or some other molecule that might be used to help cancer cells respond better to gemcitabine. “The idea is to try to identify a small [inhibitor] molecule that binds to this receptor and blocks its activity in pancreatic cancer cells.” The bad news, he says, is that it remains unclear which small molecule is responsible for VDR’s activity in pancreatic cancer. “We have a target, but we don’t yet know how to inactivate it,” he says. “Finding a drug that can inactivate VDR is a priority.”
Whether the discovery of VDR activity in pancreatic cancer cells applies to other types of cancers is not clear and will require testing. VDR may not be hijacked in other cancers the same way it is in pancreatic cancer. Nevertheless, the principle may be the same—other cancer types hijack different genes, retasking them to help survive. “We are hoping that once our paper circulates within the scientific community, it may give some new insights for experts from the field who are addressing very important questions about the influence of sunlight, vitamin D intake, and other factors on cancer risk.”