WHEN cancer cells mutate and become resistant to a “magic bullet” treatment, there may sometimes be a simple solution – fire more bullets at them.
Richard Van Etten and his colleagues at Harvard Medical School and the University of California, Los Angeles, have found that not all mutations in cancer cells have the same effect, and it may be possible to overcome drug resistance in some cases by increasing the dose.
The findings are especially important because they concern Glivec, the first of a new generation of the anticancer drugs hailed as magic bullets. Traditional cancer drugs take the scattergun approach, wiping out all rapidly dividing cells regardless of whether they are healthy or cancerous.
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But Glivec kills only cancer cells. It binds to and blocks an abnormal enzyme found in some kinds of cancerous tissue (91av, 1 December 2001, p 30). For one type of leukaemia, it produces remission in an unprecedented 90 per cent of patients.
However, in some people it fails because a few cancer cells become resistant, usually when the enzyme targeted by Glivec acquires mutations. “We’re seeing lots of mutations,” says Brian Druker of Oregon Health Sciences University In Portland, who developed Glivec. Before the new findings, only one of these mutations had been discovered and investigated. It makes cells resistant to Glivec by preventing the drug from binding to the enzyme.
Now Van Etten’s team has shown that another mutation makes it harder, but not impossible, for Glivec to bind to the enzyme (Proceedings of the National Academy of Sciences, vol 99, p 10,700). This means that some patients who appear resistant may simply need a higher dose, says Van Etten. He suggests that doctors could analyse samples from resistant patients to find out if they carry the new mutation, and those patients could be treated with a higher dose.
Because Glivec has a very specific action, it has few side effects, so higher doses needn’t cause problems. “In practice, that’s what some doctors have been doing anyway,” says Van Etten.
He says that resistance to drugs like Glivec will probably be quite common. These new drugs act on a single target, so all it takes is one mutation in a single cancer cell to overcome their effects. That’s why the most effective therapies will ultimately involve drug cocktails that target several proteins at a time, adds Druker.