5 Questions for David M. Sabatini
David M. Sabatini, MD. PhD, is a principal investigator at the Sabatini Lab at the Whitehead Institute for Biomedical Research and associate professor of biology at Massachusetts Institute of Technology (MIT). His research into the mTOR pathway has led to the identification of numerous components of this pathway, as well as its cellular and organismal functions. He is a recipient of the 2009 Paul Marks Prize for Cancer Research, among numerous other distinctions.
What role does mTOR signaling play in normal cells?
In normal cells, mTOR is essential for cells to generate and accumulate mass, and therefore grow (ie, increase in size). It is one of the central growth-promoting pathways in all cells.
How important is it in cancer development?
mTOR is also a key growth regulator in cancer cells. In addition, there are many cancer-causing mutations (in tumor suppressors and oncogenes) that lead to mTOR activation—so that it is estimated that 60% to 80% of tumors have hyperactive mTOR signaling.
Are there any currently available mTOR-targeted treatments?
Yes. The best-known mTOR inhibitor is a molecule called rapamycin, and there are also derivatives of rapamycin that are in clinical use. These molecules are used as immunosuppressants, blockers of coronary vessel restenosis in drug-eluting stents, and as treatments for cancer. They also have potential uses in neurodegenerative diseases.
Which components of the mTOR pathway do they target?
They all target the mTOR kinase, which is the central component of the pathway. They are allosteric inhibitors of mTOR.
What is the future for mTOR signaling in cancer research?
The key will be to identify which cancers are particularly sensitive to mTOR inhibitors. Currently, we know that many cancers exhibit mTOR hyperactivation, but not all respond equally to mTOR inhibitors. What is most needed is the identification of a cancer-specific mutation that causes cancers to be addicted to mTOR activity.
The wealth of literature describing the mammalian target of rapamycin (mTOR) features a common analogy: that mTOR is a “master switch,” “central regulator,” or “key integrator” of cell growth and proliferation. Therefore, it is unsurprising to find that aberrant mTOR signaling is implicated in the pathogenesis of cancer and has attracted substantial interest from researchers since its discovery 20 years ago.
The mTOR Complexes
mTOR is a serine/threonine kinase that exists in 2 multiprotein complexes, mTORC1 and mTORC2, defined by the different component proteins bound to mTOR. Both complexes consist of mTOR and the mLST8 and Deptor proteins. mTORC1 also contains the regulatory-associated protein of mTOR (Raptor) and the proline-rich Akt substrate of 40kDa (PRAS40) protein. mTORC2 contains the rapamycin-insensitive companion of mTOR (Rictor), mammalian stress-activated kinase-interacting protein 1 (mSin1), and the protein Protor.
Rapamycin, available since the mid-1970s, is a naturally occurring inhibitor originally isolated from a strain of the soil bacterium Streptomyces hygroscopicus and was initially used as an immunosuppressive drug. The discovery of 2 yeast genes, TOR1 and TOR2, led to the identification and cloning of mTOR. And, once mTOR was implicated in cancer, researchers turned their attention to the role of rapamycin in cancer development.
The exact mechanism of rapamycin inhibition remains unclear; it forms a complex with FKBP12 (FK506-binding protein of 12kDa) and mTOR. It is believed that only mTORC1 is infl uenced by rapamycin. However, recent evidence suggests that mTORC2 may also be susceptible to prolonged rapamycin exposure.
mTOR Pathway Activators and Effectors
Conserved from yeast to man, mTOR integrates incoming signals from nutrient and energy sensors on the cell surface with activation of cellular machinery to regulate growth and proliferation, ensuring that these processes happen only under appropriate conditions. mTOR receives signaling input from growth factors, hormones (eg, insulin), nutrients (eg, amino acids), cellular energy levels, and stress conditions.
A principal signaling pathway that activates mTORC1 is the phosphatidylinositol 3-kinase/ protein kinase B (PI3K/Akt) pathway, which is well known for its central role in cell survival and proliferation. In the context of mTOR signaling, activated Akt phosphorylates and inhibits the tuberous sclerosis complex (TSC) and PRAS40, both of which are negative regulators of mTORC1, thereby activating mTORC1.