PI3K-Like Protein Kinases
What is the potential of TOR inhibition for cancer therapy?
Dr Mike Hall - University of Basel, Basel, Switzerland
We discovered TOR, the TOR protein in the early 1990s, 1991; we discovered it taking a genetic approach with yeast, making the assumption that it was a very highly conserved protein, conserved all the way from yeast to human and therefore we could use yeast as an experimental system to identify it. The advantage of using yeast, of course, is that you could do genetics which you couldn’t do with mammalian cells in those days. This turned out to be a good idea by the post-doc in the lab at the time because it in fact allowed us to discover TOR which was a rather competitive area in those days.
Are there two types of TOR?
There are two flavours of TOR in the sense that TOR is found in two structurally and functionally distinct complexes which, like TOR itself, are very highly conserved, again from yeast to human. These two TOR complexes which we also discovered but much later, in 2002, control different cellular processes. We call these TOR complex 1 in mammals, we call them mammalian TOR complex 1 and mammalian or mTOR complex 2 in this case. mTORC1 is rapamycin sensitive, so TOR the acronym stands for target of rapamycin, and rapamycin binds and inhibits the TOR which is a kinase, a nutrient and growth factor activated kinase. So rapamycin binds and inhibits TOR complex1 but not TOR complex 2.
As a consequence of binding inhibiting TOR complex 1, it blocks the major function of TOR which is to control cell growth which is why rapamycin has been developed as an anti-cancer drug for treatment originally for renal cell carcinoma.
Is rapamycin used as a cancer drug?
It’s used, it’s not as effective as everybody thought it would be given the central role of TOR in controlling cell growth. But I should say that cancer drugs in general are not that effective, they give short-term benefit but they don’t really cure cancer. We’re not there yet. I think the great hope lies in using combinations, the right combinations on the right cancers. I think rapamycin will ultimately be an effective cancer drug but in combination with other drugs.
What is the link between ageing and cancer, relative to TOR?
We know that, as I said, TOR is a nutrient and growth factor activated kinase. As a nutrient activated kinase it’s a nutrient sensor. It doesn’t sense nutrients directly but it senses the nutrients. The effect of rapamycin, if you downregulate it or you block it with rapamycin, is you mimic starvation, you induce a starvation state or what we could call a dietary restriction state. We know that dietary restriction extends lifespan and this has been known since 1935 but the molecular basis of that was not known. Now we know that downregulating TOR extends lifespan and, given TOR is a nutrient sensor and downregulating TOR mimics dietary restriction, the molecular mechanism of dietary restriction extending lifespan is inhibition of TOR signalling. Now the link to cancer, cancer is an age related disease and there the link becomes obvious.
