New insight into cancer-associated liver enzymes could boost drug development

San Diego
New findings from UC San Diego help explain why some enzyme inhibitors don't work in liver cancer.

Researchers at the University of California San Diego School of Medicine have found that the role of cancer-promoting and cancer-inhibiting enzymes is more complex than previously thought. The new findings improve the understanding of how liver cancer develops and could lead to better therapies for the disease.

“When it comes to liver cancer, I think we’ve been making strategic mistakes,” senior author Gen-Sheng Feng, professor of pathology and biological sciences at UC San Diego, said in a statement. “In cancer development, we always thought about two distinct families of enzymes—one promotes cancer, one inhibits it. Many drugs have been developed to block the cancer-promoting pathways, but we and others are now finding that many classical pro-cancer proteins are actually inhibitors.”

Feng’s team conducted multiple studies around the enzyme Shp2, which is known to drive tumor formation. One study found that deleting both Shp2 and the tumor-suppressing enzyme Pten, curbed leukemia development. But another study found, counterintuitively, that removing this cancer enzyme actually promoted liver cancer. In the latest study, removing both enzymes in mouse models caused liver tumors to form earlier and liver disease to be more severe than it was in mice who retained one or both enzymes.

Mice lacking one of the enzymes developed tumors seven or 12 months later. But all of the mice that had neither enzyme developed tumors at seven months, with 80% of them developing tumors within five months, according to the statement.

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The researchers then tested their hypothesis in human liver cancer samples. Analyzing 335 samples, they found half of them had low levels of Shp2 and Pten. Four years after surgery, 60% of these patients were still alive, compared to 90% of the patients who had high levels of the enzymes. This helps to explain why drugs that block overactive enzymes fail to treat liver cancer, according to the statement.

“These pathways, when overactivated, stimulate [liver] tumor development, but so does inhibiting them,” Feng said. That’s why we can't rush to conclusions like we have in the past.”

In addition to providing greater insight into how liver cancer develops, the research also resulted in a new mouse model for studying liver disease. Now, instead of using carcinogens to induce liver cancer in mice, Feng’s team will create “more realistic” models by deleting Pten and Shp2. They will use the model to untangle the underlying mechanisms of liver disease and cancer as they seek new drug targets, Feng said.