KRAS is the most commonly activated oncogene across all solid tumors, and activating KRAS mutations can occur in just about any solid tumor type. But they are most frequent feature in pancreatic cancer patients, where such mutations can be found in the majority of patients, with some studies reporting rates of up to 95%.

Now, investigators at MD Anderson Cancer Center have published data suggesting that activating KRAS mutations may be selected for in pancreatitis, because they protect pancreatic tissue from damage.

"This is probably one of the first demonstrations that a driver tumor mutation can have a physiological role in maintaining the integrity of the tissue during damage and repair," Andrea Viale told BioWorld Science.

Viale is an assistant professor of genomic medicine at MD Anderson and the corresponding author of the paper describing the findings, which appeared in the September 17, 2021, issue of Science.

In showing that role, the study "redefines our understanding of the cooperation of inflammation and oncogenes," Viale added. Specifically, "we do not need an active, ongoing inflammation to cooperate with KRAS."

Who's driving, and what's the destination

Inflammation increases the risk of many types of cancer, and pancreatic inflammation or pancreatitis is a major risk factor for the development of pancreatic cancer.

In addition to inflammation, outright pancreatic cancer is preceded by a malleable state called acinar ductal metaplasia.

However, though mutated KRAS can induce acinar ductal metaplasia, the phenomenon can also occur when there are no oncogenic mutations. Activating mutations of KRAS, on the other hand, have "been described early in acinar cells in patients with pancreatitis, long before the development of a tumor... probably decades before," Viale said.

Those disconnects prompted the investigators to look at the physiological role of acinar ductal metaplasia and its relationship to inflammation and KRAS-driven tumors in more detail.

In their experiments, the researchers first showed that when it first occurred, pancreatitis could "reprogram cells epigenetically and transcriptomically for a very long time," long after the pancreatitis itself had resolved. Mechanistically, the reprogramming was driven by the transcription factor early growth response protein 1 (EGR1), which was expressed in response to IL-6 secreted by proinflammatory macrophages.

"In mouse, this lasts for months," Viale said, so in humans, the same reprogramming is likely to persist for "many years."

That reprogramming enabled the cells to limit tissue damage if pancreatitis recurred. Acinar cells produce digestive enzymes, and ductal cells transport those enzymes through the bile ducts. By switching from an acinar to a ductal cell, "basically, these cells stop producing the enzyme that can fuel and maintain the pancreatitis," Viale said.

But if a KRAS mutation occurred, even after the inflammation had resolved, that same reprogramming primed the cells for transformation into tumor cells.

The reason is that acinar ductal metaplasia "is mediated by the activation of MAP kinases," Viale explained. "And KRAS is there. It is on the same pathway."

In other words, activating KRAS mutations ensure a strong protective response in recurring pancreatitis -- under circumstances where KRAS activated the MAP kinase pathway, Viale said, "we do not have any tissue damage at all."

Given their protective effects, Viale and his team believe that activating KRAS mutations are likely to be under strong positive selective pressure, though he noted that "we didn't demonstrate that [KRAS mutations] get selected for, this is something we are working on."

If that assumption turns out to be correct, then it may be possible to prevent KRAS-driven pancreatic cancer by pharmacologically inducing acinar ductal metaplasia. Viale and his colleagues are currently working on identifying pharmacological ways to induce reversible metaplasia.

By preventing the tissue damage, this approach could cure the pancreatitis itself -- and in doing so, remove the selective advantage of KRAS mutations.