Researchers identify target for cancer drugs

Feb 23 2005

For nearly a decade, scientists have been trying to fully understand a particular communication pathway inside of cells that contributes to many malignant brain and prostate cancers. While scientists have identified elements of this pathway, other key components have remained a mystery.

Researchers at Whitehead Institute now have discovered a missing puzzle piece, a finding that may present drug makers with a significant new cancer target.

"We believe that we have identified a component that researchers have been looking for since 1996," says Whitehead Associate Member David Sabatini, who is also an Assistant Professor of Biology at MIT.

At the heart of this new research is a protein called Akt, an important player in the regulation of cell division and survival. Abnormally high activation of Akt has long been implicated in a variety of cancers. If Akt travels to the cell membrane, it is switched on and promotes cell division, often contributing to tumor growth as a result. However, as long as it stays within the cell cytoplasm, it remains relatively inactive. That's because the tumor-suppressor protein PTEN keeps Akt in check by destroying lipids in the cell membrane that normally draw Akt to the surface. In a sense, PTEN keeps a leash on Akt and thus suppresses cell division.

But when PTEN is mutated and unable to function, Akt breaks free. It makes its way to the cell membrane where other proteins activate it, thereby enabling Akt to contribute to tumor growth. "When a cell loses PTEN through, say, a mutation, Akt goes gangbusters," says Sabatini.

The exact means by which Akt switches on when it reaches the cell membrane has only been partially understood. As a result, researchers have lacked a clear idea about how to prevent the process. However, in the February 18 issue of the journal Science, researchers from the Sabatini lab report on discovering an important missing piece of the activation process.

This missing component, a molecule called mTOR, is a protein that influences a cell's ability to expand in size. mTOR has been widely studied as the target for the immunosuppressant drug rapamycin (in fact, mTOR is an acronym for "mammalian target of rapamycin"). In July of 2004, Dos Sarbassov, a scientist in Sabatini's lab, discovered a new protein that mTOR interacts with called rictor, but he wasn't yet sure of what these two proteins do together. In this latest paper, Sarbassov reports that when mTOR and rictor bind and form a complex, they help activate Akt by adding a phosphate group to a sequence of its amino acids (a process called "phosphorylation").

This process occurs not only in human cells but in other organisms such as the fruit fly. Finding this complex conserved in species as diverse as flies and humans supports the claim that the mTOR/rictor complex is indeed a missing piece of the puzzle.

According to Sarbassov, "If we find a molecule that can block the mTOR/rictor complex, then we may be able to prevent Akt from becoming active and contributing to tumor formation."