Therapies that Target mTOR May Enable Some Cancer Cells to Grow

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Cancer biologist Wilhelm Palm

Cancer biologist Wilhelm Palm

Targeted therapies that block a protein called mTOR have greatly improved the outcome for people with certain cancers, especially kidney and some blood cancers. But for other types of cancer, many of which were expected to respond to these drugs based on early research in cell cultures, the results have been disappointing.

Now a study from a team led by Memorial Sloan Kettering President Craig B. Thompson is providing clues about why that is the case.

“Five years ago there was a lot of enthusiasm for these drugs,” explains Wilhelm Palm, a postdoctoral researcher in Dr. Thompson’s lab and the paper’s first author. “This study is the first explanation of why they don’t work as well as expected, especially for pancreatic cancer.”

An Alternate Source of Nutrients

“Cancer cells consume a lot of nutrients, which they need to grow and proliferate,” Dr. Palm says. “Normally those nutrients are sugars and free amino acids, which they get from the blood.” But the investigators found that for some kinds of tumors, blocking mTOR may actually allow cancer cells to take their energy from a source that is not usually available to them: extracellular proteins, which are found in the area surrounding the cells.

MSK President and CEO Craig Thompson

MSK President and CEO Craig Thompson

Single-celled organisms such as amoeba are known to use proteins as an energy source to fuel their growth. This type of metabolism is not commonly seen in mammalian cells, but recent studies have suggested that some cancer cells, including those with mutations in the gene K-Ras, may be able to use extracellular proteins for energy while suppressing apoptosis (programmed cell death) at the same time.

In the new research, published recently in the journal Cell, the investigators found that mTOR proteins prevent cancer cells from degrading extracellular protein and using it as an energy source. This means an mTOR inhibitor might actually make it easier for cancer cells to grow by removing this restriction. This could be especially true for those cells that have K-Ras mutations or are nutrient starved because they don’t have easy access to a blood supply.

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Helping Cancer Cells to Adapt

“There was hope that mTOR inhibitors would be effective against pancreatic cancer, but that has not been the case,” Dr. Palm says. In fact, the new research showed in mouse models that pancreatic cancers with K-Ras mutations actually grow faster when they are given mTOR-inhibiting drugs.

“We’ve found that cancer cells are more adaptable with nutrients than we expected,” he continues. “They are very flexible and resilient.”

Cancer cells are more adaptable with nutrients than we expected.
Wilhelm Palm postdoctoral fellow

Inhibitors of mTOR are effective in kidney cancer because those cancers — unlike some other tumors — have mutations in the mTOR pathway that drive them to become cancerous. And because blood cancers have easy access to nutrients in the bloodstream, mTOR inhibitors have no effect on how they get their energy. For other cancers, blocking mTOR may actually help the cancer cells tap the extracellular proteins for nutrients.

The investigators say their findings point toward the possibility of new combination therapies. “You could combine mTOR inhibitors with another type of drug called a lysosome inhibitor, which could prevent the cancer cell from hydrolyzing [breaking down] protein,” Dr. Palm says. So far, this combination has only been tested in cell cultures, but the team is planning further research in this area. 

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This research was funded by the National Cancer Institute under grants P01 CA104838 and P30 CA008748. It was also funded by an EMBO Long-Term Fellowship and a Genentech Foundation Hope Funds for Cancer Research fellowship, both awarded to Dr. Palm.