Researchers pinpoint critical weakness in colon cancer

By Haley Bridger, Broad Communications, September 14th, 2008
Achilles
Image courtesy of Wikimedia

Cancer can seem like an unrelenting, unassailable beast, but, like any opponent, it has its weaknesses. Researchers at the Broad Institute, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and elsewhere are working to find those weak points and exploit them as part of “Project Achilles.” Named after a warrior from Greek mythology whose one weak spot led to his undoing, Project Achilles brings together distinct yet complementary genomics techniques to discover the molecular underpinnings of cancer. The group’s latest achievement, described in the September 14 advance online edition of the journal Nature, is the discovery of a gene involved in a substantial fraction of colon cancer cases. Because this gene normally functions as a kind of molecular switch known as a kinase, the researchers propose that it represents an attractive new target for potential cancer therapies.

Using a combination of approaches, the researchers systematically combed through the genomes of colon cancer cells to find genes potentially related to colon cancer. Tumor DNA may contain thousands of mutations; however, only a handful of these mutations are thought to contribute to cancer growth. The rest, according to senior author of the Nature paper and Broad Institute Senior Associate Member Bill Hahn, are just along for the ride. But, figuring out which genes are just “passengers” and which are “drivers” can be a daunting task.

In previous work under Project Achilles, researchers discovered that the gene IKBKE may be one of the key drivers of breast cancer. They used a series of three techniques to find the breast cancer gene. In the case of colon cancer, the researchers once again used multiple tactics to narrow in on a target. “The fundamental challenge of genomics is, once you have thousands of candidate genes, how do you triangulate on one critical target?” said Jesse Boehm, a research scientist at the Broad Institute working on the Project Achilles team. “In this case, the combination of functional and structural genomics approaches was able to do that.”

Flipping the off switch

The researchers relied heavily on a genomic technique known as RNA interference (RNAi) to ferret out genes potentially involved in colon cancers. Drawing on the resources and expertise of the Broad’s RNAi platform, this technique enabled the researchers to shut off individual genes, one at a time, in order to determine the ones critical to colon cancer cells. Hahn, who is also an associate professor at Harvard Medical School and Dana-Farber Cancer Institute, has compared this to switching off circuit breakers to determine which one controls a particular electronic device.

In almost all cases of colorectal cancer, a transcription factor called β-catenin appears to be overly active and contributes to tumor growth. Author Ron Firestein, a pathologist at Dana Farber Cancer Institute and Brigham and Women’s Hospital who works closely with the Broad’s RNAi Platform, said that the platform researchers used this information to identify key genes that affect the pathway: they switched off each gene, and watched to see what effect, if any, it had on the activity of β-catenin.

“Since such a high percentage of colon cancers are characterized by abnormally high activity of a single pathway, we had a simpler model,” said Firestein. “This gave us the opportunity to identify which genes are necessary for the activity of this pathway in cancer cells."

In parallel, the team also searched for genes that are essential for the rapid growth of colon cancer cells. Comparing the results from the two different screens revealed an overlap of just nine genes, including a cyclin-dependent kinase called CDK8.

Looking for an overlap

A telltale sign of an oncogene, or one of the genes “driving” cancer, is extra copies of the gene. While researchers were using RNAi techniques to find promising oncogenes, Adam Bass, a member of Broad Senior associate member Matthew Meyerson’s laboratory and a medical oncologist at Dana Farber Cancer Institute, had been looking at the colon cancer genome from a different perspective. Bass wanted to find areas that were amplified to help determine what regions of the colon cancer genome might be harboring oncogenes. Bass heard about the Project Achilles research on colon cancer while he was working at the Broad Institute last year. The researchers shared their data, looking for genes that had come up in both their searches. CDK8 immediately stood out.

Bass explained that the researchers’ ability to home in on the gene had less to do with luck and more to do with the collaborative atmosphere of the Institute.

“There was clearly some luck in that Ron and I both independently had results pointing to the importance of CDK8 in colorectal cancer,” he said. “But in research there are probably many such instances where this occurs but the connection is never made. I like to think that the culture of the Broad Institute encourages people to talk to each other and share data across labs — even new and unpublished data — and thus makes it more likely that they will make connections that push research ahead.”

When the researchers took cells with normal levels of the gene and increased the activity of CDK8, the healthy cells became tumor-like. But turning off CDK8’s kinase activity successfully prevented rapid cell growth in six different colon cancer cell lines. This indicated that it might be possible to develop a drug that could turn off the kinase’s activity in cancer cells.

According to the researchers, the discovery of this previously unsuspected gene is exciting for several reasons. “Anytime we find a new mutation like this one, it’s a reminder that there is still so much yet to be discovered,” said Hahn. “CDK8 is a particularly exciting target because it is found at elevated levels in nearly half the cases of colorectal cancer.” Unlike transcription factors, a kinase like CDK8 is a potentially good therapeutic target, meaning that in the future, researchers may be able to design drugs that take aim at the oncogene, dealing a powerful blow to colon cancer.

Many additional Broad researchers contributed to the new Project Achilles work including So Young Kim, Ian Dunn, Serena Silver, Isil Guney, Milan Chheda, Pablo Tamayo, Yashaswi Shrestha, Craig Mermel, Jordi Barretina, Jennifer Chan, David Root, and Matthew Meyerson.

Paper(s) cited: 

Boehm et al. (2007) Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell DOI:10.1016/j.cell.2007.03.052

Firestein et al. (2008) CDK8 is a colorectal cancer oncogene that regulates β-catenin activity. Nature doi:10.1038/nature07179