Inhibiting the PI3K/Akt/mTOR Signaling Pathways

In This Section:

• PI3K/Akt/mTOR Signaling in Normal Cells
• PI3K/Akt/mTOR Signaling in Cancer Cells
• Inhibiting PI3K/Akt/mTOR Signaling
• Self Test

PI3K/Akt/mTOR Signaling in Normal Cells

mTOR is a critical regulator of several normal cell processes in numerous cell types, including cells of the immune system. Several other proteins—including PI3-kinase, Akt and PTEN—play roles in mTOR signaling.

A cross-section of a cell is shown, including the membrane and some cytoplasm. Proteins in the cytoplasm are labeled PTEN, PI3-kinase, mTOR, and Akt.

PI3-kinase is an enzyme that phosphorylates certain phospholipids of the cell membrane. Once phosphorylated, these phospholipids bind to a protein called Akt. Akt then becomes phosphorylated and activated. This triggers activation of several downstream signaling pathways, which increases cell survival, proliferation, and cell growth.

A cross-section of a cell is shown, including the membrane and some cytoplasm. The protein Akt is associated with a phospholipid in the cell membrane. Arrows representing signaling pathways extend from Akt and are labeled “Increased Survival,”” “Increased Proliferation,” and “Increased Growth.”

One important player in the growth and proliferation pathways is mTOR. When activated by Akt, mTOR promotes cell growth and proliferation by stimulating protein synthesis.

A cross-section of a cell is shown, including the membrane and some cytoplasm. The protein Akt is associated with a phospholipid in the cell membrane. Arrows representing signaling pathways extend from Akt and are labeled “Increased Survival,” “Increased Proliferation,” and “Increased Growth.” The mTOR protein is shown as part of the “Increased Growth” and “Increased Proliferation” pathways. The label “Increased Protein Synthesis” indicates how mTOR participates in these pathways.

In addition to receiving signals from Akt, mTOR monitors the cell’s environment for the presence of growth factors and nutrients. If the cell needs additional resources, mTOR can increase nutrient uptake and promote angiogenesis. mTOR can also increase the activity of Akt, thus enhancing the other downstream effects of this protein.

A cross-section of a cell is shown, including the membrane and some cytoplasm. The protein Akt is associated with a phospholipid in the cell membrane. Arrows representing signaling pathways extend from Akt and are labeled “Increased Survival,” “Increased Proliferation,” and “Increased Growth.” The mTOR protein is shown as part of the “Increased Growth” and “Increased Proliferation” pathways. Small blue molecules outside the cell are labeled, “Growth Factors, Nutrients” and a blue arrow leads into the cell from these molecules to mTOR, indicating that mTOR monitors levels of these molecules. Arrows leading from mTOR are labeled “Increased Nutrient Uptake” and “Increased Angiogenesis.”

Because mTOR and its signaling partners are so powerful, the cell has mechanisms in place to regulate them. One important watchdog is PTEN. PTEN removes the phosphate groups added to membrane phospholipids by PI3-kinase. This prevents activation of Akt and its downstream pathways.

The Akt and mTOR pathways are shown, but are gray, indicating that they are inactive. The protein PTEN is associated with a membrane phospholipid and Akt has dissociated from the membrane.

PI3K/Akt/mTOR Signaling in Cancer Cells

The signaling pathway that includes mTOR is highly active in many cancer cells. This can be the result of amplification or mutation of the PI3-kinase gene, amplification or mutation of the Akt gene, or loss of function of PTEN. Increased activity of some growth factor receptors can also enhance the activity of the pathway.

A cross section of a green cancer cell is shown, including the cell membrane and cytoplasm. Akt, mTOR, PI3-kinase and PTEN are shown to indicate that alterations in these proteins have been found in cancer.

In addition, growth and proliferation of many types of cancer, including lymphomas, are driven by proteins and cell processes that depend on proteins regulated by mTOR.

Inhibiting PI3K/Akt/mTOR Signaling

Drugs targeting PI3-kinase, Akt, and mTOR are being tested in preclinical models and clinical trials. One mTOR inhibitor is a small molecule called rapamycin. Rapamycin enters the cell and binds to a protein called FKBP12.

A close-up of a cancer cell is shown. A pathway containing Akt and mTOR is shown activated. The small molecule rapamycin, represented by a small purple oval, is bound to a protein labeled FKBP12.

This complex binds to and inhibits mTOR. Inhibition of mTOR with rapamycin has been found to inhibit proliferation of several types of lymphoma cells.

A close-up of a cancer cell is shown with a pathway containing Akt and mTOR visible. A complex of rapamycin bound to FKBP12 is interacting with mTOR. Elements of the signaling pathway downstream of mTOR are gray, indicating that rapamycin-FKBP12 prevents mTOR from activating downstream pathway members.

mTOR inhibitors, including rapamycin, are being tested in clinical trials for lymphoma.

A group of green figures on the right of the screen represent clinical trials participants. Three gray boxes on the left of the screen are labeled, “Phase 0,” “Phase I,” and “Phase II” and are connected by arrows.

Some of these trials are using mTOR inhibitors in combination with standard therapies or other targeted therapies, such as Rituxan®. Researchers are also working to develop assays to identify patients in whose tumors mTOR or its signaling partners are highly activated because these patients may be more likely to benefit from treatment with combinations of therapies that include mTOR inhibitors.

Self Test

Questions

1. mTOR is involved in the following cellular process(es):
   1. Protein synthesis
   2. Nutrient uptake
   3. Both A and B

Answers

1. Correct Answer: c
2. 1. Partially correct.
      mTOR does play a role in protein synthesis, but it can also influence a cell’s uptake of nutrients.
   2. Partially correct.
      mTOR does play a role in nutrient uptake, but it also influences protein synthesis.
   3. Correct.
      mTOR is involved in both protein synthesis and nutrient uptake.