Howard Hughes Medical Institute researchers have identified many potential new drug targets for cancers long deemed "untouchable" due to the type of genetic mutation they contain. These studies are beginning to reveal new ways of attacking cancer by targeting a largely hidden network of normal genes that cancer cells rely on for survival.
Independent research teams led by Howard Hughes Medical Institute (HHMI) investigators D. Gary Gilliland of Brigham and Women's Hospital (now senior vice president at Merck Research Laboratories) and Stephen J. Elledge at Harvard Medical School, used RNA interference (RNAi) technology to identify a host of genes that cancer cells depend on for survival. The researchers studied cells with mutations in KRAS, the most commonly mutated gene in human cancers.
KRAS, which was discovered nearly 30 years ago, is mutated in 30 percent of human tumors, including 90 percent of pancreatic cancers, 50 percent of colon cancers, and 30 percent of non-small cell lung cancers.
"Efforts to develop drugs that inhibit oncogenic RAS proteins have been largely unsuccessful, despite the fact that RAS gene family members are mutated in about 30 percent of human tumors," said Gilliland, who directs the oncology program at Merck.
More than 18 months ago, Elledge and Gilliland decided to see if they could use the powerful RNAi technology to seek out genes that KRAS-mutant cancer cells need for survival. Their efforts, culminating in two reports in the May 29, 2009, issue of the journal Cell, have led to the identification of potentially promising drug targets: serine/threonine kinase 33 (STK33) and polo-like kinase 1 (PLK-1), as well as a host of other proteins.
"These targets represent a potential Achilles heel for tumors," said Gilliland. "In the case of STK33, it is absolutely required for survival of cancer cells. Normal cells don't require it."
"The translational implications of both re
|Contact: Jim Keeley|
Howard Hughes Medical Institute