"What makes this discovery significant is that we've found mutations that directly affect cancer development," says Victor Velculescu, M.D., Ph.D., senior author of the study and assistant professor at the Johns Hopkins Kimmel Cancer Center. "Most gene discoveries today focus on finding increased or decreased activity of a gene that may not affect cancer progression, akin to passengers on a bus that can't control the bus' speed or direction. What we've found are the brakes of the bus."
After analyzing 157 colon cancers, the research team found 77 mutations in six genes that make tyrosine phosphatases, enzymes that help coordinate signals that manage cellular growth, death, differentiation, and nearby tissue invasion. They normally work by turning off tumor growth, as so-called tumor suppressors, but in cancers these genes are mutated and no longer work properly. Because it is difficult to restore a mutated suppressor gene with cancer drugs, the investigators believe phosphatases themselves are not good drug targets. Yet, for every tyrosine phosphatase there is a matching enzyme, called a tyrosine kinase, which plays an opposite role, turning a pathway on and accelerating cellular events.
"If a bus' brakes are broken and they can't be fixed, another way to slow it down is to let up on the accelerator," explains Velculescu. "In this case, the faulty brakes are mutated tyrosine phosphatases and the accelerators are the tyrosine kinases." Tyrosine kinas
Contact: Vanessa Wasta
Johns Hopkins Medical Institutions