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No Through Road

Cancer cells are able to find new pathways around targeted therapies. Scientists are racing to get there first. By Sue Rochman

What would you do if you were in your car on the way to a family celebration and found yourself trapped in a traffic jam? A generation ago, you probably would have pulled out a map. Today, you’d probably rely on GPS or a smartphone to see your options. And as you selected a route around the blockade, you’d be doing precisely what cancer cells have done since time immemorial.

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That’s because a cancer cell is equipped with something akin to a real-time Google Street View car, allowing the rogue cell to identify alternate routes it can take or build when a cancer drug disrupts or blocks its primary path of survival. What’s more, each time a cancer cell learns how to get past one treatment, it becomes better prepared to outsmart another. The medical term for a cancer cell’s ability to outmaneuver a cancer therapy is drug resistance, and it is ultimately responsible for many of the cancer deaths that occur.
Overcoming drug resistance is not a new goal, but over the past five years, as targeted therapies have seen more success, ideas about how to tackle resistance have begun changing. By tracking how cancer cells respond when they face a barricade, scientists may finally be able to learn how to outfox them.
Anticipating the Enemy
The scientific advances that led to targeted therapies, which block a specific growth mechanism inside a cancer cell, have opened up new ways of thinking about drug resistance. “Insights into targeted therapies have come much more quickly” than they did for chemotherapy, when it comes to understanding drug resistance, says Charles Sawyers, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York City. “By definition, targeted therapies have targets, so when resistance develops, the natural first question is whether there is some change in the target. … So while it can sound discouraging that you make a targeted therapy and the tumor is outsmarting the drug, the good news is that we know the enemy and we know what the likely first line of defense will be—and we can anticipate it.”
Sawyers’ team started thinking about how cancer cells would get around Xtandi before the drug was given to patients.
That’s precisely what the researchers in Sawyers’ laboratory at Memorial Sloan-Kettering are trying to do: predict what a cancer cell will do next, and then figure out a drug that will block its end run. Their first success was in chronic myeloid leukemia (CML), a cancer of the white blood cells. Sawyers’ laboratory had played a critical role in the development of Gleevec (imatinib), the first drug developed specifically to block a molecule in a cancer cell—in this case a protein called bcr-abl—known to fuel the cell’s growth.
Gleevec transformed CML from a death sentence into a manageable illness, catapulting the drug to the cover of Time magazine in 2001. Then, a problem emerged. In some patients, the drug stopped working—the cancer had identified the blockade and found a detour. Enter Sawyers. Using the same technology that led to Gleevec, his team soon found that the resistant cancer cells had developed mutations that changed the shape of the bcr-abl protein that Gleevec targeted. This discovery led to Sprycel (dasatinib), a targeted therapy granted accelerated approval in 2006 that is given to patients whose cancer cells are no longer responding to treatment because they have learned how to get past the barricade that Gleevec puts in their way.
Sawyers is now using a similar technology to identify the tricks that metastatic prostate cancer uses to get around the androgen receptor antagonist Xtandi (enzalutamide), which was approved in August 2012 to treat men who had already been on the chemotherapy drug Taxotere (docetaxel). Sawyers’ team began developing Xtandi in 2004, and he started thinking about how cancer cells would learn to get around it even before the drug was given to patients.


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