The study, published in the Sept. 10 issue of Cancer Cell, overturns the current belief that a mutation in the KRAS oncogene is enough to initiate pancreatic cancer and unrestrained cell growth.
The findings uncover critical clues on:
– how pancreatic cancer develops,
– why few patients benefit from current therapies,
– how to improve treatment and prevention of pancreatic cancer
The research team, led by Howard C. Crawford, Ph.D., a cancer biologist at Mayo Clinic’s campus in Florida, and Jens Siveke, M.D., at Technical University in Munich, Germany, found that for pancreatic cancer to form, mutated KRAS must recruit a second player: the epidermal growth factor receptor, or EGFR. A third genetic participant known as Trp53 makes pancreatic tumors very difficult to treat, the study showed.
The scientists also found that EGFR was required in pancreatic cancer initiated by pancreatic inflammation known as pancreatitis.
“The perfect storm needed to trigger pancreatic cancer include KRAS mutations and inflammation in the organ, which then work synergistically to turn on EGFR,” says Dr. Crawford.
“The bottom line is, without EGFR, tumors don’t form — and that was never known before this study,” he says.
“Inflammation in the pancreas has a big impact on turning on EGFR.”
The researchers discovered that when they blocked EGFR activity, the mice studied were protected against developing chronic pancreatitis and pancreatic cancer.
They further found that in mice that had lost expression of the TP53 tumor suppressor — a situation that mirrors up to 60 percent of human pancreatic cancer cases — tumors escape the dependency on EGFR for initiation and continued growth of pancreatic cancer, Dr. Crawford says.
Pancreatic cancer is a highly lethal disease; no drug has been able to target the mutant KRAS protein. The study suggests some patients, such as those with chronic pancreatitis, may be good candidates for treatment with EGFR inhibitors to fight or prevent pancreatic cancer, Dr. Crawford says.
“The clinical implications of this study are exciting. It suggests that pancreatic cancer patients with normal p53 activity, as well as patients with chronic pancreatitis, may be good candidates for treatment with EGFR inhibitors,” Dr. Crawford says.
“These findings give us some greatly needed clues about how pancreatic cancer develops and progresses,” Dr. Crawford says. “The more we understand about these early tumors, the more we will be able to work on diagnosis and therapy.”