Protein targeted by drug developers not open and shut case

CAMBRIDGE, Mass. — Discovery of the mTOR protein and the role it plays in cell growth, a process often linked to diseases such as cancer, was part serendipity and part good detective work. And like any good whodunit, the mTOR story wouldn’t be complete without an unexpected twist.

The mTOR story begins with rapamycin, an immunosuppressant used to prevent organ rejection in transplant patients. Initially, doctors knew rapamycin was effective but didn’t know exactly why. Scientists then discovered that rapamycin works by blocking the activity of a protein responsible for sensing nutrients in a cell’s environment. By inhibiting this protein, rapamycin tricks cells responsible for organ rejection into believing that they are starving, causing them to stop growing. Scientists dubbed the protein mTOR, mammalian target of rapamycin.

Studies conducted in Whitehead scientist David Sabatini’s lab found that rapamycin was inhibiting a complex of proteins that, together with mTOR, sense nutrients and control cell growth. As Sabatini and others studied mTOR in greater depth, its role in disease became more apparent, raising hopes that mTOR could be targeted by drug therapy. But new research from the Sabatini lab suggests that the investigation into mTOR’s function is far from over.

“When you completely snuff out mTOR activity, cells die. Yet, rapamycin, which we know inhibits mTOR, isn’t overtly toxic to patients or cells in culture," says Dos Sarbassov, a postdoc in Sabatini’s lab. This, he says, suggests that rapamycin does not inhibit the essential mTOR function.

In the July 27 issue of Current Biology, the group reported the discovery of a protein, called rictor, that helps explain why rapamycin is not toxic to patients and provides new evidence that mTOR plays a more complex role in the cell than previously thought. Despite rapamycin’s destructive effect on some mTOR proteins, mTOR that is bound to rictor remains unaffected and able to perform other jobs within the cell.

“When given to patients, rapamycin is inhibiting only a fraction of mTOR’s activity,” says Sabatini. “This has important ramifications for pharmaceutical companies developing drugs to inhibit mTOR activity.” Researchers in the Sabatini lab currently are investigating what other roles mTOR may play in mammalian cells.

Citation

Sarbassov, D. D., Ali, S. M., Kim, D. H., Guertin, D. A., Latek, R. R., Erdjument-Bromage, H., ... & Sabatini, D. M. (2004). Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Current biology, 14(14), 1296-1302.