K. O'Reilly et al., "mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt," Cancer Res, 66:1500—8, 2006. (Cited in 95 papers)
It's known that rapamycin inhibits lymphoma growth but not solid tumor growth. Rapamycin activates Akt — an enzyme upstream of the protein mTOR, which is crucial to cell survival. In 2006, Sloan-Kettering oncologist Neal Rosen and collaborators illustrated in human tumor cells that inhibiting mTOR does indeed activate Akt. In addition, they short-circuited Akt-mediated cell survival by blocking upstream insulin-like growth factor (IGF)-I, while inhibiting mTOR, and showed improved antitumor action of rapamycin.
Hitting the mTOR pathway in two places in tumor cells decelerates cell growth while speeding up cell death. "You're kind of putting your foot on the accelerator and the brake at the same time," explains David Sabatini of the Whitehead...
Sabatini warns that the mTOR pathway is still a black box in many ways. "There are alternative explanations out there that explain why rapamycin is not a panacea," he says. Recent evidence shows that rapamycin inhibits only some of the different variants of mTOR, potentially explaining its varying antitumor effects.
In 2007, Peter Houghton's group at St. Jude's Children's Research Hospital effectively targeted tumors in vivo in animal sarcoma models with a combination of drugs that inhibit mTOR while activating Akt. "Blocking the IGF-I receptor combined with rapamycin is very synergistic in about half of the sarcoma models we've looked at," Houghton says.
|Cell culture results after three days of treatment|
|Treatment with||Tumor Cell Count|
|Rapamycin action alone||~ 70,000|
|IGF-1 inhibitors alone||~ 65,000|
|Rapamycin and IGF-1 inhibitors||~ 40,000|