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Cancer Drug Zeroes In on a Genetic Mistake

An experimental compound shrank lung-cancer tumors in half of the patients in a recent study.
October 28, 2010

At some point in Karen Pihl’s life, one of her lung cells made a potentially fatal misstep. As the cell duplicated its DNA in preparation to divide, part of the gene for one protein became erroneously attached to part of the gene for another. The genetic malfunction bestowed the cell with the ability to grow out of control, ultimately creating lung cancer.

Shrinking cancer: An experimental drug that targets a particular genetic mutation shrank one patient’s tumor, as shown in this CT scan of the lungs before (top) and after (bottom) treatment. (This patient had previously had part of the lower left lung removed.)

Today, Pihl is part of a clinical trial, being published in the New England Journal of Medicine, of an experimental lung cancer drug that specifically blocks the effects of that mutation. According to the findings, the drug, called crizotinib and developed by Pfizer, shrank tumors in half of patients whose cancers carried a similar genetic mistake. The drug suppressed tumor growth in another third.

While larger studies are still needed before the drug can be approved by the U.S. Food and Drug Administration, researchers hope it will provide a more effective and less toxic alternative for the approximately 2 to 7 percent of patients with non-small-cell lung cancer that carry this mutation. Traditional chemotherapies can affect both healthy and cancerous cells, leading to severe side effects. But targeted drugs such as this one act only on cancer cells, which typically means the drugs are much easier for patients to tolerate.

Pihl underwent chemotherapy and radiation therapy after her initial diagnosis in 2004, only to have her cancer return. Seeking a second opinion, Pihl went to Massachusetts General Hospital in Boston, where her doctor screened her cancer cells for specific genetic mutations that might render it susceptible to experimental drugs.

Three weeks later, Pihl received news that she was eligible for an ongoing clinical trial of the Pfizer compound. She began taking the experimental drug in March 2009 and has been on it ever since. “Each scan showed a decrease in the size of tumors, and the last scan showed scant remains or nothing,” she says. In contrast to the chemo and radiation, “the side effects of the drug have been so minimal for me,” she says.

Scientists have long known that cancer cells flourish thanks to an accumulation of genetic mutations that allow the cells to grow out of control. With advances in genomics technologies, including cheaper gene sequencing and microarrays designed to detect specific genetic sequences, the number of known genetic mutations linked to cancer is growing rapidly.

These studies have revealed that individual tumors carry a unique profile of genetic mutations, which in turn has led to an entirely new way to classify cancers. In addition to looking at the shape of cancer cells and other traits visible under a microscope, as is typically done today, scientists can use molecular tools to search for specific genetic variations.

These markers are increasingly being used to predict a patient’s prognosis and to select the drugs that will be most effective in tackling the particular molecular mistakes underlying their cancers. Pihl’s specific mutation creates what’s known as a fusion protein, when the genes for two proteins are mistakenly joined. First discovered in 2007 by Hiroyuki Mano, a scientist at the University of Tokyo, Pihl’s mutation tacked half a protein called EML4 onto a receptor known as ALK. The outcome is a permanently activated receptor “which continuously sends out proliferation signals that directly lead to cancer,” says Mano.

Mice engineered to express the fusion protein in their lungs quickly develop hundreds of cancer nodules. In fact, the protein generates cancer much more quickly than other genetic aberrations linked to the disease. “It is an early and principle event” in the development of cancer, says Mano.

Mano’s studies suggest that the fusion is responsible for about 4 to 5 percent of non-small-cell lung cancers (the most common type of lung cancer) in Asians. The frequency appears to be slightly lower in other groups. It is more common in cancer patients who are young, who have never smoked, and whose tumors lack the EGFR mutation, another mutation found in some lung cancers.

Pfizer already had a compound designed to block the activity of the ALK enzyme in clinical trials when scientists there learned of Mano’s discovery of the fusion protein. Researchers running clinical trials of the drug, including a group at Mass General Hospital, quickly opened their studies to patients with the EML4-ALK fusion. In the most recent study, which focused on 82 patients with the mutation, the treatment shrank tumor size in at least 47 and blocked tumor growth in 27 patients. Sixty-three patients, including Pihl, are still taking the drug, some for as long as two years. Unlike chemotherapy, patients take these drugs for the long-term, or until they stop working. A larger study of the drug is already underway.

“Most patients have tolerated the drug quite well,” says Eunice Kwak, an oncologist at the Mass General Hospital Cancer Center. Kwak led the study. “For those with side effects from their tumors, it allowed them to resume a normal life.”

The study is among the first to focus on a genetically defined group of cancer patients early on. Drugmakers say this approach makes it cheaper and faster to show that a particular drug works. In this case, about 80 percent of the patients in the study responded to the drug, a better rate than most tests of new cancer drugs, and much higher than would have been the case in an unselected population. “That makes a big difference; not treating patients who we don’t think will benefit from the drug,” says Keith Wilner, senior director of oncology clinical development at Pfizer. The company is collaborating with Abbott to develop a diagnostic that will be paired with the drug.

“There’s a good chance [the drug] will be approved by the FDA in the next few years, which is very fast,” says Jeffrey Engelman, director of the Center for Thoracic Cancers at MGH’s cancer center. “We’re well posed to see the clinical benefit of this drug, which will help thousands of patients over the next few years.”

It’s not yet clear why 20 percent of people with the mutation do not respond to the drug, but scientists speculate that their tumors have additional mutations that render them resistant. And as tests of other targeted cancer therapies have shown, most patients who initially respond to these drugs eventually evolve resistance. The time it takes to become resistant varies tremendously; some patients respond for years, others only for a few months.

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