Breakthrough identifies genes for resistance to MEK inhibitors in colorectal cancer

A research team has discovered how two genes cause colorectal cancer cells to become resistant to treatments used against the disease. The activity of the two genes, MEK and MET, was uncovered when the researchers looked at all the different pathways and interactions taking place in colorectal cancer cells.

Sandra van Schaeybroeck, PhD, and her research team at Queen's University in Belfast, Ireland, published this breakthrough in Cell Reports (2014; doi:10.1016/j.celrep.2014.05.032). The researchers found that these colorectal cancers switch on a survival mechanism when they are treated with drugs that target faulty MEK genes. But when the researchers added drugs that also block the MET gene, the colorectal cancer cells died.

The current study used in vitro, in vivo, clinical, and publicly available gene-expression data to identify pathways that KRAS-driven colorectal cancer requires and that mediate resistance to MEK inhibition and chemotherapy. The researchers developed both in vitro and in vivo data, and their data supports moving forward with trials in patients. The team is now testing a new approach to target these two genes in the most aggressive forms of colorectal cancer in a clinical trial, funded by the European Commission, which is being led by van Schaeybroeck.

More than half of patients with colorectal cancer develop the aggressive form of the disease which does not respond to standard therapy. The 5-year overall survival for those with aggressive disease is less than 5%.

"We have discovered how two key genes contribute to aggressive bowel cancer. Understanding how they are involved in development of the disease has also primed the development of a potential new treatment approach for this disease," said van Schaeybroeck.

The clinical trial, which is called MErCuRIC and is due to start in September, will deliver personalized medicine to Northern Irish patients and patients from other European countries. Overall, the pan-European collaborative effort will involve 13 research/clinical teams from nine European countries.

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