BOSTON and CAMBRIDGE--Cancer cells fueled by the mutant KRAS oncogene, which makes them notoriously difficult to treat, can be killed by blocking a more vulnerable genetic partner of KRAS, report scientists at the Dana-Farber Cancer Institute and the Broad Institute of Harvard and MIT.
The laboratory results, published by Nature on its Web site as an advanced online publication and later in a print edition, demonstrate a potential advance against many major tumors which, because they harbor the mutant KRAS cancer gene, are highly aggressive and respond poorly to treatment. By targeting the second, more easily inhibited "co-dependent" gene, TBK, the strategy bypasses the so far unfruitful head-on assault against the highly resistant KRAS gene.
"These results represent a new way of targeting oncogenes that have been refractory to standard treatments," said William Hahn, MD, PhD, senior author of the report, of Dana-Farber, the Broad Institute, and Harvard Medical School (HMS). "What's particularly exciting is that this approach is potentially highly specific to cancer cells, and therefore should have little toxicity to normal tissues."
The first author is David Barbie, MD, of the two institutes and HMS.
The mutant KRAS oncogene acts like a broken switch, allowing runaway cell growth in nearly all pancreatic tumors, about 25 percent of colorectal, and 25 to 30 percent of lung cancers. When physicians detect KRAS mutations in a cancer, it usually predicts the patient won't respond well to standard therapies. "If you have a mutant KRAS, we can't use many of our newest drugs," noted Hahn.
For many years, researchers were hopeful that drugs could be designed to shut down KRAS, but this has proven virtually impossible. However, its co-dependent partner, TBK1, encodes a protein kinase -- a type of molecular switch for which many inhibitors already exist. TBK1 is not a cancer-causing gene, but in KRAS-driven tumors, TB
|Contact: Bill Schaller|
Dana-Farber Cancer Institute