Researchers close in on new way to treat aggressive bowel cancers

In collaboration with the Press Association

Targeting a "previously unappreciated" protein could lead to a treatment for aggressive bowel cancers, US researchers have found.

The finding, published in the journal Cell, could apply to up to a quarter of people who develop the disease.

But UK experts warned that, while the research was exciting, drugs targeting TAK1 - previously linked to inflammation - could be some years away.

Two genes - APC and KRAS - drive most bowel cancers. Around eight out of ten bowel cancers carries a faulty APC gene, whereas about half have a faulty KRAS gene.

Cancers in which both of these genes are defective are generally hardest to treat, and new-generation targeted treatments like cetuximab tend not to work in these patients.

Bowel cancers with faulty KRAS genes can be further subdivided into 'KRAS-dependent' cancers - in which blocking KRAS kills the cancer cells - and 'KRAS-independent' cancers.

But drugs that target KRAS directly have proven elusive.

Scientists at the Massachusetts General Hospital Cancer Center investigated how to kill bowel cancer cells in that had a defective APC gene and were also dependent on KRAS.

In lab experiments, they showed that TAK1 protein was a key player behind the growth of KRAS-dependent cancer cells.

Blocking the protein's activity killed these cells by triggering cell 'suicide' called apoptosis.

They also revealed the molecular signals behind this process, and showed that blocking TAK1 in mice that had cancers caused by fault APC and KRAS, shrunk these cancers.

Dr Daniel Haber, co-author of the study, said: "This study shows that if you understand the interrelationships between all the signaling pathways in a particular type of tumour, you may uncover a vulnerability".

He added that the TAK1 inhibitor they used in this study was not suitable for patients, but pharmaceutical companies have developed chemicals that block TAK1 inhibitors.

These have not yet been developed because their potential application was not clear, he said.

Work will now take place that could lead to clinical trials of TAK1 inhibitors are being planned.

Professor Owen Sansom, a cell signaling expert from Cancer Research UK's Beatson Institute, said the finding was exciting and could potentially lead to new treatments for aggressive bowel cancer.

"The TAK1 protein has previously been linked to inflammation, but this is the first time it has been shown to play a key role in cancer," he added.

"People whose bowel cancer is driven by a mutant KRAS gene tend to have the least favourable outlook, and new-generation targeted therapies like cetuximab aren't generally effective. 

"These results suggest that, in theory, drugs that block TAK1 could be helpful for at least a proportion of these patients."

Copyright Press Association 2012

References

  • Singh, A., Sweeney, M., Yu, M., Burger, A., Greninger, P., Benes, C., Haber, D., & Settleman, J. (2012). TAK1 Inhibition Promotes Apoptosis in KRAS-Dependent Colon Cancers Cell, 148 (4), 639-650 DOI: 10.1016/j.cell.2011.12.033