Many roads to resistance
Cancer cells usually divide rapidly and mutate often. This makes their DNA subject to many random changes, some of which allow the cells to evade the therapy and survive. Scientists have identified a long list of resistance mechanisms, with new ones cropping up from time to time. To list a few:
- The cancer cell "amplifies," or makes numerous extra copies of the molecule that is targeted by the cancer drug. As doctors increase the drug dose to compensate, the toxic side effects on the patient may become too intense to continue. For example, the target of a commonly used cancer drug, methotrexate, is an enzyme called DFHR that's needed by rapidly dividing cancer cells. Resistance develops when cells mutate and make many extra copies of the DFHR gene, overwhelming the methotrexate.
- A molecule in cancer cells that is the attack point for a particular drug may morph into a mutant form that isn't vulnerable to the drug. The molecule may even disappear from the cell, which nevertheless remains cancerous.
- Chemotherapy agents entering cancer cells can be ejected by tiny "pumps" in the pores of the cells' membranes. These pumps have evolved to clear the cell of harmful substances. Overactivity of the genes that spur cells to make such pumps can create "multidrug resistance," in which cells eject several kinds of chemotherapy agents. The chief culprit here is the pump gene known as MDR-1.
- Cancer cells may get rid of molecules that normally help ferry cancer drugs into cells.
- Drugs that disable cancer cells by damaging their DNA may become less potent because the cell speeds up its DNA damagerepair process.
- Large solid tumors thwart cancer drugs by their sheer size; the cancer is beyond the reach of the small blood vessels through which the chemotherapy agents are delivered to the tumor.
Drug-resistant cancer cells multiply as the single-drug therapy kills off only the original tumor cells (those without shields).
Scientists at Dana-Farber, other research centers, and pharmaceutical companies are continually dissecting drug resistance mechanisms and exploring ways to make cancer cells vulnerable once more. It's an endless race to plug the hole in the therapeutic dike—and then the next one, and then the one after that.
One form of counterattack is to create new combinations that hit the tumor from several different directions, aiming to knock out all the nascent populations of resilient cells. Researchers also have been working hard over the past decade on ways of weakening the cellular pumps, but even though they've found some compounds that accomplish the task—such as cyclosporin, which poisons the pump—this remains a work in progress.
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