The important gene – K-Ras – is one of the most commonly mutated genes in cancer. But it has been difficult to develop inhibitors of mutated K-Ras because of the structure of the molecule.
But now, a team based at Cancer Research UK’s Cambridge Research Institute have shown that C-Raf is needed for mutated K-Ras to encourage the growth of lung cancer.
This opens up a completely new avenue of research looking at ways to block the growth of lung cancer, bypassing the K-Ras gene.
Professor David Tuveson, lead author of the study, said: “The K-Ras gene has presented us with a difficult problem for lung cancer and other cancers where K-Ras is mutated, like pancreatic and bowel cancer. It’s known as an ‘undruggable’ gene – drugs developed to target and block the protein produced by the mutated gene have, to date, failed to do so.
“Our discovery may provide us with a solution to this problem. We now know that K-Ras can’t promote lung cancer development without the enzyme C-Raf.
“It’s an exciting result and we’ll be taking this research further to see if blocking C-Raf can be a feasible way to stop the cancer-causing effects of K-Ras.”
Dr Florian Karreth, first author of the study, said: “Under normal conditions, B-Raf seems to be the major player. So we were surprised to find that instead K-Ras depends on C-Raf to initiate lung cancer.”
The researchers used genetic techniques to get rid of two enzymes – C-Raf and B-Raf – in mice and in lung cells in the laboratory. They found that when B-Raf was knocked out, it had no effect on whether K-Ras was able to turn normal cells into cancer cells. But when C-Raf was removed, cancer development was prevented.
Mutations in Ras genes are seen in around 30 per cent of all tumours and K-Ras is the most common type of Ras mutation.
Dr Lesley Walker, director of cancer information at Cancer Research UK, said: “As we’re learning more about the genetics of cancer, we’re starting to uncover just how complex it is.
“The discovery of K-Ras was an important milestone but it turned out to be more difficult to target than we initially thought. This study offers us a way to target the gene through the ‘back door’.”
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- C-Raf is required for the initiation of lung cancer by K-RasG12D. Karreth et al. Cancer Discovery. 11 May 2011.