Genetic Mutation Confirmed as Melanoma Drug Target
9 June 2010 - A mutation present in around half of malignant melanomas has been confirmed as a strong drug target, according to research published today in Science Translation Medicine.
Several drugs that target the BRAF mutation have already reached clinical trial in patients with this deadly form of skin cancer, and some are showing promising results. However, it has not been clear whether their effectiveness was from inhibiting BRAF as designed or for another reason. In addition, the first drug to be trialled in melanoma patients, sorafenib, was halted during Phase III testing after it failed to show a survival benefit, adding uncertainty over the importance of damaged BRAF in such cases.
To determine how these drugs were working, Professor Richard Marais and colleagues at the ICR constructed models using drug-resistant forms of the BRAF protein. They then tested whether the drugs retained their anti-cancer activity on tumour cells with these damaged proteins. These studies show that sorafenib, a first-generation drug, does not work in melanoma because it does not target the damaged form of BRAF in tumours, whereas a second-generation drug called PLX4720 works in melanoma because it does target damaged BRAF.
“We have absolutely confirmed that BRAF is an important drug target for malignant melanoma, and that the clinical benefit from these second-generation drugs is due to their ability to target the damaged BRAF protein,” Professor Marais says.
