I was wondering about resistance mechanisms that arise when humans take drugs, specifically with respect to the anti-cancer drug Glivec. How does this work?
Some background: Glivec is a rare success story in the effort to develop targetted cancer drugs. Chromic myelogenous leukemia (CML) is an unusual cancer in that it presents a unique target for inhibition - an overactive kinase enzyme that is caused by a genetic abnormality in CML sufferers. As a result, the right drug molecule can be extremely selective and have few side effects. Compare this to an old school cytotoxic chemotherapeutic, basically an unselective poison that kills cancer cells at a faster rate than it kills other cells in the human body.
Some people acquire resistance to glivec through mutating the key kinase target. I don’t really understand how this resistance mechanism works in a human body. Bacterial resistance to, say, antibiotics, is intuitively easy to grasp because the rate of bacterial reproduction is so high. It must be several orders of magnitude greater than for a human and provides the selection pressure over a short timescale. Where does the selection pressure (if that is the right term, seen as we’re not talking about generations) come from in the case of the Glivec - kinase binding event? It seems like there is not the window of opportunity for mutation / selection to take place?
Actually, that’s not that hard to understand. The cells that mutate live - the cells that don’t mutate die. Survival of the fittest. It’s evolution on a very small scale.
I’m ignorant, but my wife happens to be an authority on cancer drug mechanisms. Here’s her response.
I was half-right about spelling. Gleevec and Glivec are both correct - one is the domestic brand, the other is the international.
Cancerous cells, by definition, are rapidly dividing and reproducing cells. And these are white blood cells which are constantly being regenerated even in their non-cancerous state. This is what generates the number of “events” needed for mutations to arise.
Keep in mind, too, that Gleevec was designed to fit into a mutated enzyme of a specific configuration and jam it. Any change, even one subunit of that enzyme where the drug molecule is designed to fit will change the configuration of the enzyme. Thus Gleevec stops working. I believe a second drug has been developed to deal with a relatively common change in the mutated enzyme. As such, the loss of effectiveness is due to the enzyme mutating because of an active cancer cell, not because Gleevec causes the mutation to occur.