Researchers discover a weakness in a rare cancer that could be exploited with drugs

The cancer cells are, in some ways, impressive: they can grow relentlessly, avoid the aging process by becoming immortal and escape the persistent attacks of the immune system. But in the process of acquiring these superpowers, cells sometimes have to give up other more mundane skills, including the ability to produce certain nutrients.

Researchers at Rockefeller University are now announcing the discovery of a rare tumor type, unable to synthesize cholesterol, a molecule without which cells can not survive.

"These cells become dependent on the absorption of cholesterol in their environment, and we can use this addiction to design therapies that block the absorption of cholesterol," said Kivanç Birsoy, an adjunct professor at Chapman Perelman, who presents the results in Nature.

Reduce cholesterol

Birsoy has long been fascinated by the fact that, in rare cases, cancers lose the ability to produce essential nutrients. Some types of leukemia, for example, are unable to synthesize the amino acid asparagine. As the first line of defense against these cancers, doctors offer patients a drug called asparaginase, which breaks down the amino acid by removing it from the blood. Without access to the external reserves of the nutrient, the cancer cells die.

Birsoy and his colleagues, including Javier Garcia-Bermudez, a postdoctoral fellow in Birsoy's lab, have been looking for other types of cancer that might be vulnerable to cuts in nutrient supply. Researchers first became interested in cholesterol, an essential ingredient of all dividing cells. Typically, cancer cells make cholesterol themselves or obtain it from the cellular environment, where it is present as low density lipoprotein (LDL).

The researchers placed 28 different cancer cell types in a cholesterol-free environment and indicated which ones had survived. Cells badociated with a rare type of lymphoma, known as ALK-positive ALCL, did not endure these conditions, suggesting that these cells could not synthesize cholesterol by themselves.

When examining data on gene expression of cholesterol-dependent cell lines, the researchers found that these cancers lacked the enzyme involved in cholesterol synthesis. Without this enzyme, cells accumulate squalene, a poorly studied metabolite that acts as a precursor to cholesterol.

Although the inability to produce cholesterol is a bad thing, a buildup of squalene, Birsoy notes, could actually be beneficial for cancer cells. "These cells have to deal with oxidative stress in their environment, and we think that squalene is a way to increase antioxidant capacity," he said.

Exploit vulnerability

In another experiment, the researchers neutralized the LDL receptors of cancer cells, an essential means of external cholesterol absorption. As a result, the cells do not have access to the nutrient and die. This result suggests a new way to kill ALCL cells, which may become resistant to chemotherapy. "We believe that therapies that block the absorption of cholesterol may be particularly effective against drug-resistant ALCL forms," ​​says Birsoy.

In the future, researchers plan to screen for other cancers for similar vulnerabilities. According to Birsoy: "This is part of a larger strategy of looking for nutritional dependencies or deficiencies in different types of cancer."

Provided by
Rockefeller University