Dealing with KRAS Genes

KRAS mutated colon cancer pathway may become new target

(RxWiki News) Alterations in the KRAS gene make for one hellava difficult cancer foe. Colon cancers that are driven by this gene resist all known treatments. This log jam may have been busted through thanks to new research.

Massachusetts General Hospital (MGH) Cancer Center researchers have found that going after a later step in the pathway toward KRAS activity in colon cancer, may cause the cancer cells to commit suicide.

"Get regular screening for colon cancer after age 50."

Co-corresponding author of the study, Daniel Haber, M.D., Ph.D., director of the MGH Cancer Center, says, "Not all KRAS-mutant colon cancers are the same."

About half need the KRAS mutation to survive, while the other half keep on growing even when KRAS is suppressed, according to Dr. Haber.

He went on to explain, "In the KRAS-dependent tumors, we identified how the mutation augments a pathway well known to be involved in colon cancer and identified a key step toward that pathway which, if suppressed, can induce KRAS-dependent tumor cells to undergo apoptosis or programmed cell death."

KRAS mutations are seen in a number of cancers, but most often in lung and colorectal malignancies. The presence of these genes usually means that the cancer won't respond to treatment.

Drugs that block KRAS haven't been all that successful. Trying to develop other targets has been frustrating because the gene behaves differently in different cancers.

The original intent of the MGH research was to find out the percentage of KRAS colon tumors that grow because of the mutation.

Analyzing cell lines in the laboratory, researchers found that KRAS-dependent tumors have several overly active genes. Next, they learned that blocking the enzyme called TAK1 was the best way to achieve cell death and reduce the size of the tumor.

The team also discovered that a pathway involved in the development of both embyos and cancer was part of the whole process.

Dr. Haber says the value of this study was learning more about the relationships between the pathways that could lead to new targets for new drugs.

More study is needed and clinical trials have yet to be conducted before these possibilities can become reality.

"This is interesting preclinical work and suggests that targeting this pathway may be of benefit," said Adam Brufsky, M.D., Ph.D., who was not involved in this research.

"Human application is likely years away, since a TAK inhibitor needs to be developed for human use," Dr. Brufsky, professor of medicine at the University of Pittsburgh School of Medicine, told dailyRx.

This work was published in February, 2012 issue of Cell.

The study was supported by grants from the National Institutes of Health and the Lustgarten Foundation.

Co-corresponding author Jeffrey Settleman, Ph.D., formerly of the MGH and now with Genentech, Inc.