After 40 years of effort, researchers have finally succeeded in switching off one of the most common cancer-causing genetic mutations in the human body. The finding promises to improve treatment for thousands of patients with lung and colorectal cancer, and may point the way to a new generation of drugs for cancers that resist treatment.
It already is routine to test lung cancer patients for the mutation, because they are often resistant to other drugs, said Dr. John Minna, a lung cancer specialist at the University of Texas Southwestern Medical Center in Dallas. How the off-switch was discovered is a story of serendipity and persistence by an academic chemist who managed the seemingly impossible.
KRAS was different. The gene directs production of a protein that normally flexes and relaxes thousands of times a second, as if it is panting. In one position, the protein signals cells to grow; in the other, it stops the growth. With the KRAS mutation, the protein remains mostly in an “on” position, and cells are constantly forced to grow.
Their drug held the protein steady, making a crevice visible on its surface. “We never saw that pocket before,” Shokat said. The protein normally flexes and relaxes so quickly that the narrow groove had almost been impossible to see.