Navigation Links
Researchers exploit genetic 'co-dependence' to kill treatment-resistant tumor cells
Date:10/21/2009

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, TBK1 activity enables cancer cells to survive that otherwise would be destroyed by the body because they are abnormal and dangerous.

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 that you can do this in human cells."

The discoveries of TBK1 and STK33 are only the first of what the scientists expect will be many more "co-dependent" genes in cancer cells that may prove valuable as drug targets.

"We plan to screen 300 cell lines over the next couple of years," said Hahn. "The aim is to create a dataset in which any investigator can say, 'I'm looking for genes that interact with this oncogene or that tumor-suppressor gene.' Our intent is to make these data public in order to help move the field forward."

In the meantime, Hahn said there is considerable interest in testing existing kinase inhibitors as potential new therapies for KRAS tumors. He added that researchers at Dana-Farber and the Broad are interested in developing novel molecular tools to suppress the action of co-dependent oncogene partners.


'/>"/>

Contact: Bill Schaller
william_schaller@dfci.harvard.edu
617-632-5357
Dana-Farber Cancer Institute
Source:Eurekalert

Related medicine news :

1. Yerkes researchers present at 39th Annual Society for Neuroscience Conference
2. Patent challenges reduce pharmaceutical innovation and productivity, researchers suggest
3. ResearchToolkit.org provides one-stop Web resource for health researchers
4. New Professional Network Brings Chinese Scientists and Researchers into International Community
5. Pitt researchers find candidates for new HIV drugs
6. Researchers discover mechanism that helps humans see in bright and low light
7. New effort to battle antibiotic resistance rallies researchers throughout Harvard University
8. Researchers report benefits of new standard treatment study for rare pediatric brain cancer
9. Researchers identify genes associated with onset age of Parkinsons disease
10. BUSM researchers identify better laser for treating facial spider veins
11. Toronto researchers discover novel circulation in human eye, new glaucoma treatment target
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:8/18/2017)... ... August 18, 2017 , ... Mediaplanet today announces the launch ... lifestyles and highlighting the importance of proactive eye and ear health. The campaign ... latest innovations in hearing aid technology. , In this issue, the National ...
(Date:8/18/2017)... ... , ... The Dawn Johnson Insurance Group, a Missouri-based insurance and financial planning ... support for efforts to educate the local population on cancer realities while attracting donations ... , Each day in America, roughly 4,600 new cases of cancer are diagnosed ...
(Date:8/18/2017)... , ... August 18, 2017 , ... ... financial planning assistance that serves communities throughout southern Florida, is working to support ... scholarship assets to children from low income families. , The Take Stock In ...
(Date:8/18/2017)... , ... August 18, 2017 , ... “Emotions are sacred, ... Founder of St. Louis-based positive education company Generation Mindful. To help change the mindset ... learn social and emotional skills, she created the Time-In Toolkit, which launched on Kickstarter ...
(Date:8/18/2017)... SAN DIEGO, CA & CARMEL, IN (PRWEB) , ... August 18, ... ... No. 3828 on its 36th annual list, the most prestigious ranking of the nation's ... ASH has been included in the exclusive Inc. 5000 ranking . This year’s ...
Breaking Medicine News(10 mins):
(Date:8/7/2017)... GAITHERSBURG, Md. , Aug. 7, 2017 /PRNewswire/ ... for healthcare member acquisition, retention, and engagement, announced ... Director of Strategy and Product Development, effective as ... strategic consulting and technology implementation strategy for our ... years of experience in consulting and business analytics ...
(Date:8/7/2017)... -- Endo International plc (NASDAQ: ENDP ) today ... known U.S. mesh product liability claims and that it ... U.S. claims at reasonable values. Under the agreements, Endo ... of 2017 and continuing through the fourth quarter of ... the Company intends to increase its mesh product liability ...
(Date:8/2/2017)... Aug. 2, 2017 Fenita J. ... as a Pinnacle Lifetime Professional in the Field ... Manager at Turing Pharmaceuticals, AG. Her skills and ... relationship building.                ... 25 years of experience as a highly successful ...
Breaking Medicine Technology: