Why do you become refractory to a drug?

Why do you become refractory to a drug? Why do you become refractory to a drug? It's a multifaceted answer, I guess. Number one could be that the leukemia cells, possibly bring an analogy to the bacterial world. And when we treat infections, particularly if you have exposure to an antibiotic for an extended period of time, the bacteria become resistant to infections. Many times the bacteria, they try to figure out how to avoid the drug. It may be just pumping the drug out of the cell. Sometimes the leukemia cell does that, that it pumps the drug out of the cell. Number two, if the drug is targeting a vital survival pathway of the leukemia cell, say they are dependent on a particular mutation, now your drug is targeting a particular mutation, the leukemia cell can rewire the system to an extent that they will find another way to survive, not be dependent on this mutation alone. So that's another mechanism. Sometimes this ends up acquiring newer mutations. A very common situation that we see in the space of FLT3 mutation, which is one of the bad mutations in AML, but there are drugs available. Drugs like Midostorin available, Giltretinib available, and there are other drugs which are in the pipeline too. For patients who are exposed to this FLT3 inhibitor for an extended period of time, sometimes acquire additional mutations and then they become resistant. So the cell figures out a way to rewire itself or change its dependency.