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 trialed in melanoma patients, sorafenib, was last year 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.
Professor Marais says: “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. It is crucial that we understand the mechanism behind these drugs’ effects to ensure they are only given to patients with the specific genetic defects – in this case, a mutated BRAF gene – that will allow them to benefit. This knowledge may also help us combat resistance and develop new-generation drugs.”
Around 10,000 people are diagnosed with malignant melanoma each year in the UK, and around 2,300 die as the disease is difficult to treat once it has spread to other organs.
BRAF-targeting drugs may also be important in other tumour types, as mutations in this gene are common in thyroid cancer (45 per cent of cases), ovarian cancer (10 per cent), and colorectal cancers (13 per cent).
Dr Simon Vincent, Cancer Research UK’s head of research funding, said: “Results like this are so exciting because they confirm the potential of the new approach to cancer therapy. Decades of work unpicking cancer’s genetic weaknesses, and trying to turn this knowledge into treatments that can target them, are now finally bearing fruit.
“Melanoma is a cancer that can spread rapidly, and is notoriously hard to treat. Now we know that specific mutations within some melanomas can be precisely targeted, we can push forward with clinical trials to reap the benefits of this new technology.”
Media Contact: Science Press Officer Jane Bunce on 0207 153 5106 or after hours 07721 747900
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