MTOR: Uncovering the link from nutrients to growth
The mechanisms that regulate organismal growth and coordinate it with the availability of nutrients were unknown until a few decades ago. We now know that one pathway—the mechanistic target of rapamycin (mTOR) pathway—is the major nutrient-sensitive regulator of growth in animals and plays a central role in physiology, metabolism, the aging process, and common diseases. This work describes the development of the mTOR field, from its origins in studies into the mechanism of action of the drug rapamycin to our increasingly sophisticated understanding of how nutrients are sensed.
In my PNAS Inaugural Article, I describe the development of the mTOR field, starting with efforts to understand the mechanism of action of the drug rapamycin, which ∼25 y ago led to the discovery of the mTOR protein kinase. I focus on insights that we have contributed and on work that has been particularly influential to me, as well as provide some personal reflections and stories. We now appreciate that, as part of two distinct complexes, mTORC1 and mTORC2, mTOR is the major regulator of growth (mass accumulation) in animals and is the key link between the availability of nutrients in the environment and the control of most anabolic and catabolic processes. Nutrients signal to mTORC1 through the lysosome-associated Rag GTPases and their many regulators and associated cytosolic and lysosomal nutrient sensors. mTOR signaling is deregulated in common diseases, like cancer and epilepsy, and mTORC1 is a well-validated modulator of aging in multiple model organisms. There is significant excitement around using mTORC1 inhibitors to treat cancer and neurological disease and, potentially, to improve healthspan and lifespan.
I decided to use my PNAS Inaugural Article to write about the development of the mTOR field and to provide some personal recollections that highlight work that has been particularly influential to me. I suppose one writes such pieces when one has been around for a while. This appears to be the case, even though I am still surprised when someone refers to me as senior or I am asked by young scientists to talk about my career.
In the fall of 1992, I went to see Sol Snyder about a thesis project. I remember the meeting well, as I would meet with Sol one-on-one very few times during my time in his laboratory. Sol sat in a comfy office chair in the balled-up way that those of us in his laboratory found impossible to mimic, and he was quiet, knowing the power of silence (we assumed it was a trick he learned during his psychiatry training). I was nervous and blurted out that I wanted to talk about potential projects. After a bit, he said, “Well, David, we work on the brain.” That seemed like a great start, as I wanted to do neuroscience, but then more silence followed, and, as I was to learn, that meant the conversation was over. I left unsettled because the brain was obviously a big topic, meaning I was project-less. That conversation though was likely the most important scientific interaction of my career, as Sol was giving me the freedom to do whatever I wanted, which allowed me to develop my own research direction at a relatively young age. I never did end up working on the brain, but I do take some comfort in having originally purified mTOR from brains.
At that time, others in the laboratory were studying the effects of the immunosuppressant FK506 on neurons and using a structurally related molecule, rapamycin, as a negative control. We were fortunate to have rapamycin because, back then, it was not commercially available, and Sol had obtained it from Suren N. Sehgal at Wyeth-Ayerst Sehgal—widely considered the father of rapamycin and its unrelenting champion until his death in 2003—had purified the compound in 1975 from bacteria found in soil collected on Easter Island. Sehgal had very kindly sent us a large amount, but just as importantly, he had also sent a book titled “Rapamycin Bibliography” with a little note wishing us luck. That book became my inspiration. It consisted mostly of abstracts describing the remarkable antifungal, immunosuppressive, and anticancer effects of rapamycin. It was clear that rapamycin inhibited the proliferation of a wide variety of cells ranging from lymphocytes and cancer cells to various species of yeast and preferentially delayed the G1 phase of the cell cycle. I had just finished the first 2 y of medical school and had learned how the immunosuppressant cyclosporin A was revolutionizing organ transplantation. At that point, I still thought I was going to be a practicing physician, so the medical applications of rapamycin were exciting to me and inspired me to determine how rapamycin works.
Targeted Therapy Drugs for Melanoma Skin Cancer
About half of all melanomas have changes (mutations) in the BRAF gene. Melanoma cells with these changes make an altered BRAF protein that helps them grow. Some drugs target this and related proteins, such as the MEK proteins.
If you have melanoma that has spread beyond the skin, a biopsy sample of it will likely be tested to see if the cancer cells have a BRAF mutation. Drugs that target the BRAF protein (BRAF inhibitors) or the MEK proteins (MEK inhibitors) aren’t likely to work on melanomas that have a normal BRAF gene.
Most often, if a person has a BRAF mutation and needs targeted therapy, they will get both a BRAF inhibitor and a MEK inhibitor, as combining these drugs often works better than either one alone.
Vemurafenib (Zelboraf), dabrafenib (Tafinlar), and encorafenib (Braftovi) are drugs that attack the BRAF protein directly.
These drugs can shrink or slow the growth of tumors in some people whose melanoma has spread or can’t be removed completely.
Dabrafenib can also be used (along with the MEK inhibitor trametinib; see below) after surgery in people with stage III melanoma, where it can help lower the risk of the cancer coming back.
These drugs are taken as pills or capsules, once or twice a day.
Common side effects can include skin thickening, rash, itching, sensitivity to the sun, headache, fever, joint pain, fatigue, hair loss, and nausea. Less common but serious side effects can include heart rhythm problems, liver problems, kidney failure, severe allergic reactions, severe skin or eye problems, bleeding, and increased blood sugar levels.
Some people treated with these drugs develop new squamous cell skin cancers. These cancers are usually less serious than melanoma and can be treated by removing them. Still, your doctor will want to check your skin often during treatment and for several months afterward. You should also let your doctor know right away if you notice any new growths or abnormal areas on your skin.
The MEK gene works together with the BRAF gene, so drugs that block MEK proteins can also help treat melanomas with BRAF gene changes. MEK inhibitors include trametinib (Mekinist), cobimetinib (Cotellic), and binimetinib (Mektovi).
These drugs can be used to treat melanoma that has spread or can’t be removed completely.
Trametinib can also be used along with dabrafenib after surgery in people with stage III melanoma, where it can help lower the risk of the cancer coming back.
Again, the most common approach is to combine a MEK inhibitor with a BRAF inhibitor. This seems to shrink tumors for longer periods of time than using either type of drug alone. Some side effects (such as the development of other skin cancers) are actually less common with the combination.
MEK inhibitors are pills taken once or twice a day.
Common side effects can include rash, nausea, diarrhea, swelling, and sensitivity to sunlight. Rare but serious side effects can include heart lung, or liver damage; bleeding or blood clots; vision problems; muscle damage; and skin infections.
