TBK1 is the second such gene co-dependent with KRAS to be discovered: In May, a team that included Barbie, Hahn, and other researchers reported in Cell that a kinase gene, STK33, had a similar function in KRAS tumors. Senior author of that report was D. Gary Gilliland, MD, PhD of Brigham and Women's Hospital, Dana-Farber, the Broad, and HMS.
The new approach exploits a relationship between the KRAS and TBK1 genes known as "synthetic lethality." The term refers to a partnership in which two genes (usually mutated) in a cell have a combined effect that neither has by itself. In some cases, neither mutation alone will kill a cell but the presence of both is lethal.
In the case of KRAS tumors, the opposite is true: both KRAS and TBK1 must be active for the cancer cell to survive; suppressing one or the other kills the cell.
The key role of TBK1 was identified in a large-scale search using the combined resources of Dana-Farber and the Broad Institute to hunt for genes that were essential exclusively to cells with mutant KRAS, but not to cells with wild-type (non-mutant) KRAS or other normal cells.
Working with scientists in the Broad's RNAi Platform, the team used RNA interference (RNAi) methods to turn off thousands of different genes in 20 laboratory cancer and non-cancer cells. They then sought out genes that, when shut down by short pieces of RNA strands, caused KRAS cells to self-destruct, but had no effect on normal cells. The screening process first identified 45 potential candidates, which were further winnowed in a secondary screen to single out TBK1.
"Until four or five years ago, you couldn't have contemplated doing an experiment like this on so large a scale," noted Hahn. "We now have the tools that make this possible." The new paper and its predecessor "really make it clear th
|Contact: Bill Schaller|
Dana-Farber Cancer Institute