From bedside to bench—and back
Dramatic responses of lung cancer patients yield important discovery
By Richard Saltus
A team of Dana-Farber researchers including Pasi Jänne, MD, PhD, (left) and Bruce Johnson, MD, tapped both clinical observations and laboratory gene studies to solve a lung cancer mystery. The question: Why did the new drug Iressa work dramatically in about 10 percent of lung cancer patients, while failing to benefit the majority?
Any improved therapy for lung cancer—still the leading cancer killer in America—stirs interest and hope, even if it falls short of a cure. One such advance is Iressa, part of a new class of oral, highly specific "targeted" cancer drugs that was approved in 2003 after testing showed it could dramatically shrink advanced tumors with few serious side effects.
Yet Iressa's powers had severe and puzzling limitations. It worked in only 10 percent of patients with non-small cell lung cancer (NSCLC, the most common form of the disease), though Japanese patients, surprisingly, tended to fare better. Why did the drug, whose scientific name is gefitinib, fail for most but work so well in some? Could physicians learn to predict who would benefit? Did the responders' cancer somehow differ from other types?
With lung cancer killing more than 160,000 American men and women each year, it seemed imperative to pursue the mystery of the fortunate few. Within a year, Dana-Farber scientists had cracked the case.
Approaching the problem from different angles, they found that Iressa responders did, indeed, have a distinct subtype of lung cancer. The difference was a previously unknown mutation, or genetic abnormality, in the gene for a protein called the epidermal growth factor receptor, or EGFR. The mutation caused the lung cancer in the first place, but its presence also made the tumor highly vulnerable to Iressa. Scientists still can't explain exactly why.
EGFR is a kinase, a type of enzyme that often serves as a biological on-off switch in cells; it is also a receptor for molecular signals that prod cells into dividing and growing. When kinases are mutant, this switch becomes jammed in the "on" position, like a car with a stuck accelerator pedal, driving the cell into uncontrolled growth. Mutant kinases respond to certain drugs—Gleevec is a prominent example—by turning the switch off.
The mystery solved, Dana-Farber scientists led by William Sellers, MD, Bruce Johnson, MD, and Matthew Meyerson, MD, PhD, published their EGFR findings in the journal Science in April 2004. A paper by researchers from Massachusetts General Hospital, reaching the same conclusion, appeared simultaneously in the New England Journal of Medicine.
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