William Hahn, MD, PhD
Demonstrating that despite the large number of cancer-causing genes
already identified, many more remain to be found, scientists at
Dana-Farber Cancer Institute have linked a previously unsuspected gene, CDK8, to colon cancer.
The discovery of CDK8's role in cancer was made possible by
new tools for assessing the activity of specific genes, say the authors
of the new study. As these tools are further improved, the stream of
newly discovered cancer genes is expected to increase, providing new
avenues for therapy, the authors suggest. The findings are being
published as an advanced online publication by the journal Nature on Sept. 14.
"This study provides confirmation that many of the genes involved in
cancer have yet to be identified," remarked the study's senior author, William Hahn, MD, PhD,
of Dana-Farber and the Broad Institute of Harvard and M.I.T. "When it
comes to identifying gene targets for therapy, we've really only
scratched the surface."
The study is noteworthy in another respect, as well, the authors
indicated. Many of the abnormal proteins linked to cancer are known as
"transcription factors" because they're able to "read" cell DNA and use
that information for producing other cell proteins.
Although transcription factors are important regulators, this class
of proteins has proven to be impossible to target with drugs. Genes that
influence such transcription factors, however, make attractive targets
for drugs, since they can potentially disrupt the cancer process and
disable tumor cells. CDK8 is such a gene.
The new study began with a focus on a protein called Β-catenin, a
transcription factor that is overactive in nearly all colorectal
cancers. Although overactive Β-catenin plays a role in the initial
formation of tumors, other genetic abnormalities must occur for tumors
to become fully malignant.
To determine which genes control the production of Β-catenin and are
involved in the proliferation of colon cancer cells, the research team
ran three screening tests. In the first two, they used RNA interference
to shut down more than a thousand genes one by one and recorded the
instances where Β-catenin activity decreased and the cells stopped
growing. They then analyzed colon cancers for genes that had extra
When they examined where the results of the three tests overlapped, one gene stood out — CDK8, explained Hahn, who is also an associate professor of medicine at Harvard Medical School.
The protein produced from CDK8 is part of the "mediator
complex," a conglomeration of proteins that serves as a bridge for
compounds involved in gene transcription.
"This study demonstrates that blocking CDK8 interferes with the proliferation of colon cancer cells that have high levels of the CDK8 protein and overactive Β-catenin," Hahn said. "Drugs that target CDK8 may be very useful against tumors whose growth is driven by Β-catenin."
The study's lead author is Ron Firestein, MD, PhD, of Dana-Farber,
Brigham and Women's Hospital, and the Broad Institute of Harvard and
Co-authors include Adam Bass, MD, So Young Kim, PhD, Ian Dunn, MD,
Milan Chheda, MD, and Matthew Meyerson, MD, PhD, of Dana-Farber, Brigham
and Women's, and the Broad Institute; Isil Guney, PhD, Yashaswi
Shrestha, Craig Mermel, and Jordi Barretina, PhD, of Dana-Farber and the
Broad Institute; Shuji Ogino, MD, PhD, Massimo Loda, MD, and Ramesh
Shivdasani, MD, PhD, of Dana-Farber and Brigham and Women's; Jennifer
Chan, MD, of Brigham and Women's and the Broad Institute; Ellen Freed,
PhD, Natalie Vena, Supriya Jain, Emeric Bojarski, and Charles Fuchs MD,
MPH, of Dana-Farber; Azra Ligon, PhD, and Stephen Finn, MD, PhD, of
Brigham and Women's; David Root, PhD, Serena Silver, PhD, Pablo Tamayo,
PhD, and Jesse Boehm, PhD, of the Broad Institute; and Jose Baselga, MD,
Josep Tabernero, MD, of Hospital Vall D'Hebron in Barcelona, Spain.
Dana-Farber Cancer Institute (www.danafarber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National