Cysteine deprivation kills pancreatic tumor cells by ferroptosis

Cysteine deprivation kills pancreatic tumor cells by ferroptosis

A new study suggests a compound in development for a rare kidney stone disease may have potential against pancreatic cancer. The compound starves tumors of an amino acid, cysteine, which was found to be critical to the survival of pancreatic cancer cells.

The study, conducted in mice with pancreatic cancer, was published in the journal Science.

"We're very encouraged by these results," says the senior author of the study. "Pancreatic cancer is a uniquely lethal disease, with an average survival rate of just six months after diagnosis. We're in desperate need of new treatments."

Most pancreatic tumors ramp up the production of oxidants that can kill many normal cells. Yet, pancreatic tumors thrive under these toxic conditions by importing large amounts of cysteine into their cells. All cells, including pancreatic tumor cells, use cysteine to manufacture molecules that detoxify oxidants.

"Since pancreatic tumors appear to depend on cysteine import for their survival, we hypothesized that it might be possible to slow tumor growth by selectively targeting this amino acid," the senior author said.

That strategy of starving the pancreatic cancer cells of cysteine worked. When the gene that controls cysteine import was knocked out in mice with pancreatic cancer closely resembling human tumors, cutting off the cancer's supply of cysteine, the tumors stopped growing and median survival time doubled.

The researchers achieved similar results when the mice were treated with cysteinase--an experimental drug that breaks down cysteine in blood. (Cysteinase is currently being developed by researchers at the University of Texas Southwestern Medical Center for the treatment of cystinuria, a rare genetic disorder in which high levels of cysteine concentrate in the urine, causing kidney and urinary tract stones.)

Human pancreatic cancer cells also appear to be dependent on cysteine, the researchers found. When cysteinase was added to human pancreatic cancer cells in tissue culture, cancer cells died.

When starved of cysteine, the pancreatic cancers cells are killed by a process called ferroptosis, the researchers also found. Ferroptosis is a form of programmed cell death that results from oxidation damage to cell membranes. Recently discovered the ferroptosis may also be harnessed against other types of cancer.

The team also explored a detailed cellular and molecular mechanisms of ferroptosis in pancreatic cancer, in hope that this understanding might lead to additional therapeutic approaches.

The team is now planning to test whether the effect of cysteinase can be magnified by combining it with other treatments, including immunotherapy.

"Though it is not yet known if pancreatic cancers in patients are also susceptible to ferroptosis from cysteine depletion," the senior author says, "the clinical development of cysteinase for treatment of the metabolic disorder cystinuria may allow us to test the idea soon."

One of the most exciting aspects of the new study is that cysteine depletion did not appear to harm healthy, normal cells. "You might imagine that all the cells of your body need every amino acid equally, but we knew from prior studies that most normal cells need only very low levels of cysteine," says the senior author. "Our whole goal in targeting this difference between normal cells and cancer cells is to develop a treatment that is toxic to cancer and gentle on the rest of the body."