The team of scientists from Cancer Research UK’s Cambridge Research Institute made the unexpected discovery that BRAF, which is linked to around 70 per cent of melanomas and seven per cent of all cancers, is in fact controlled by a gene from the same RAF family called CRAF – which has also been linked to the disease.
It is hoped this surprising finding may help scientists improve a new generation of genetically targeted treatments for cancers including melanoma.
Faults in the BRAF gene can promote the growth of cancer cells via a pathway called the MAPK. This disruption causes cells to replicate uncontrollably, leading to tumours forming.
This study looked at a drug which represents an early version of a targeted treatment for malignant melanoma, the most dangerous form of skin cancer in patients. This drug – which targeted CRAF and to a lesser extent BRAF – wasn’t successful in patients with melanoma, despite its early promise in laboratory studies.
By showing that CRAF can interact with and prevent the activation of BRAF in melanoma cell lines, the scientists think they may have explained the disappointing results which came from the clinical trial and suggest that future treatments should selectively target the BRAF protein – leaving the CRAF to help fight cancer.
Lead author, Dr David Tuveson, head of experimental medicine laboratory at Cancer Research UK’s Cambridge Research Institute, said: “Previous studies on CRAF suggested it can cause cancerous changes to develop, so drugs were developed to tackle this. To our surprise, we can now see that CRAF actually helps control cancer in some situations, such as when the BRAF gene is mutated in melanoma. Strangely, in this case, two ‘wrongs’ make a ‘right’.
“We have learnt something very important about the interplay between these two genes. The first generation of BRAF inhibitors targeted both RAF genes, but the new generation, which are now being developed, should switch off BRAF and leave CRAF alone. If our hypothesis is correct, these drugs will have more success in controlling the cancer. But this avenue will need further investigation before we can be sure this is the case.”
Dr Lesley Walker, Cancer Research UK’s director of cancer information, said: “Drugs which target the genetic faults driving cancer are extremely exciting and it is important that their potential is fulfilled. This area or research is particularly important for malignant melanoma because it can be difficult to control effectively with current treatments.
“But as this study shows, targeting these genes is extremely complicated as they interact with each other in intricate ways. An increased understanding of this process will help to improve the next generation of treatments, enabling them to work more effectively.”
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Karreth, K.A. et al, C-Raf Inhibits MAPK Activation and Transformation by B-Raf (2009). Molecular Cell.