How Pancreatic Cancer Cells Resist Chemotherapy

Cells found to hijack vitamin D receptors to repair damage caused by therapy.

Researchers have discovered how pancreatic cancer cells are able to overcome damage caused by chemotherapy.

In a study published in the January 3, 2015 issue of Cell Cycle, investigators examined how the cancer cells are able to hijack the vitamin D receptor to re-purpose it in order to repair damage caused by chemotherapy.

Most pancreatic cancer patients are treated with gemcitabine, which prevents cells from replicating their DNA and blocking tumor cells from dividing, thereby causing them to die off. Numerous patients die within a few months, however, due to their cancer finding a way to work around treatment.

"Maybe there is something we don't understand about how gemcitabine works," said lead researcher Timothy J. Yen, PhD, in a press release. "More likely, cancer cells have found a way to avoid DNA-damaging drugs."

In order to evaluate how pancreatic cancers overcome chemotherapy and gemcitabine treatment, the researchers removed each of the 24,000 genes in pancreatic cancer cells. They then exposed the cells to gemcitabine to examine what caused cells to become more sensitive to the drug, which revealed a significant “knockout” gene that normally binds to vitamin D.

When this vitamin D receptor in cancer cells was inactivated and gemcitabine was added, nearly all of the cells died, which identified a key mechanism that impacts the effectiveness of chemotherapy in fighting pancreatic cancer, according to the study.

“If we find a drug that inactivates the vitamin D receptor, it may allow gemcitabine to selectively kill pancreatic cancer cells while leaving healthy cells unharmed," Dr. Yen said. "Patients would just need to drink lots of milk or take calcium supplements to make sure their bones stay healthy."

While pancreatic cancer cells need the vitamin D receptor to survive, normal cells don't, which means that future cancer treatments can take out the receptor without causing much damage or side effects given that patients take calcium supplements to ensure healthy bones.

"By knocking out the vitamin D receptor, we could inactivate that DNA repair process that is allowing drug-treated tumor cells to live. As a result, we could eliminate more cancer cells at the outset," Dr. Yen said. "The Pancreatic Cancer Action Network has launched an initiative to double patients' survival by 2020; with this new finding, we believe it's a step in the right direction."