October 17, 2019 • 3 Min

Dousing Out-of-Control KRAS Signaling in Pancreatic Cancer

Researcher Rene Bernard

When cancer cells divide and grow out of control, it is often the result of a communication breakdown along a long chain of proteins and activating enzymes.

One way to think of it is like a bucket brigade, the way fires were fought before hand-pumped fire engines. The success of the extinguishing effort depended on the cooperation of a chain of stationary firefighters, each passing along a bucket of water. When the fire is out, the call for more buckets of water stops. Normally, cell division is controlled by signals from proteins and enzymes. When something goes wrong with the signaling, the cell division goes out of control and a cancer occurs.

In pancreatic cancer, the chain in question is the MAPK (mitogen-activated protein kinase) cell signaling pathway. When the MAPK pathway operates properly, the proteins and enzymes pass signals down the line to the end, where a gene is activated to induce cell division and proliferation. When the upstream signal stops, the activation stops.

In most cases of pancreatic cancer, a mutated KRAS protein remains active, always transmitting signals, even when it shouldn’t be, even when the other proteins and enzymes have stopped. As a result, the cells at the endpoint divide out of control, causing chaos.

Scientists have studied this pathway for a while and have tried targeting it again and again by stopping individual bucket holders along the chain. One of the enzymes that comes after KRAS in the chain, MEK (mitogen-activated protein kinase kinase), has been an especially popular drug target. But any effect of inhibiting MEK on its own has not lasted long; the cells develop resistance mechanisms to bypass the blockade.

Breaking Through on Either Side of KRAS

A team of scientists in Germany and the Netherlands believes it may have found a work-around. Led by internationally lauded cancer researcher René Bernards, Ph.D., of the Netherlands Cancer Institute in Amsterdam, the group is taking a two-pronged approach, targeting the MAPK pathway both upstream and downstream of KRAS.

Preclinical work, funded last year via a $1 million grant from the Pancreatic Cancer Collective (a collaboration between the Lustgarten Foundation and Stand Up To Cancer) identified a promising upstream target: SHP2.

SHP2 (also known as PTPN11), links receptor tyrosine kinase signaling to the MAPK pathway. By using one drug to inhibit SHP2’s ability to pass on signals to KRAS, combined with another drug to inhibit MEK’s ability to receive them further down the line, the researchers have seen success at preventing rampant cell proliferation in mouse models.

The next step will be testing the drug combination in humans. Bernards is teaming up with the lab of Hana Algül, M.D., Ph.D., of Technical University Munich, Germany, to begin clinical trials. First, they will have to establish safe doses of the two drugs. Then they can begin to test the combination’s effectiveness in pancreatic cancer patients, nearly all of whom have KRAS mutations.

Bernards noted that last year’s discovery of the potential importance of SHP2 in the MAPK pathway was a fortuitous one, as U.S. pharmaceutical company Revolution Medicines had just developed a small molecule to inhibit SHP2. He has been working closely with Revolution Medicines, as well as the provider of an MEK inhibitor, to secure both drugs for his trial, and he hopes to be able to enroll the first patients next year.

Bernards, who has been recognized with many prestigious awards for his fundamental contributions to the fields of genetics and molecular biology, is eager to begin this next step on the path to clinical translation of his science.

“I feel a very strong societal obligation to push my discoveries into the clinic,” Bernards says. “In the end I want to see that my discoveries are translated into better clinical protocols that have a direct impact on the lives of patients.”