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Characterising the BRAF gene

We played a major role in characterising the BRAF gene and its role in cancer, increasing our understanding of malignant melanoma.

Our work on the gene and the structure of the BRAF protein underpinned the discovery of drugs that target BRAF such as vemurafenib and dabrafenib, which have been recommended for use on the NHS.

Bioassay (Jan Chlebik for the ICR 2011)

Photo: Jan Chlebik for the ICR 2011

In the early 1990s, a team of researchers at The Institute of Cancer Research, London led by Professor Chris Marshall began studying a cell signalling pathway involved in controlling cell growth.

Their research increased our knowledge of the pathway – known as the RAS/RAF/MEK/ERK pathway – and its role in cancer, and helped identify targets for new classes of cancer drugs.

Building on this research, Professors Marshall and Richard Marais – who at the time was a colleague at the ICR – conducted further experiments on the pathway. They predicted that a protein called BRAF could play a role in cancer development.

BRAF as a driver of cancer

In 2001, they teamed up with colleagues at The Wellcome Trust Sanger Institute to investigate BRAF in more detail. They found that BRAF mutations are present in a number of cancers, including approximately 50% of melanomas.

They then went on to confirm mutated BRAF as an oncogene capable of driving the development of cancer even in the absence of other major genetic defects.

The overactive BRAF protein now looked like an attractive drug target.

Professors David Barford and Marais at the ICR made an important scientific step by elucidating the detailed molecular structure of the mutant protein. This helped pharmaceutical companies develop selective inhibitors of mutated BRAF – including vemurafenib and dabrafenib, which have been approved to treat melanoma.

These treatments are frequently initially successful, although usually the cancers become resistant to the treatment within a year.

Success in the clinic

Research teams led by Professors Marais and Caroline Springer observed that some patients who were taking selective BRAF inhibitors developed another type of tumour as a side-effect.

Drawing upon these findings, other researchers suggested that combining BRAF inhibitors with another treatment type known as MEK inhibitors could improve outcomes compared to selective BRAF inhibitors alone and this combination has showed success in the clinic.

Professors Marais and Springer researched alternative types of inhibitors, aiming to overcome resistance to selective BRAF inhibitors. They discovered that so-called ‘panRAF’ inhibitors have advantages in overcoming resistance to selective BRAF inhibitors. Their clinical candidate is currently being assessed in trials at The Royal Marsden NHS Foundation Trust and Christie Hospital.

The development of targeted therapies based on ICR research has significantly improved outcomes for patients with malignant melanoma. The availability of diagnostic tests means that doctors can select the most appropriate treatment for patients depending on the mutations in their tumours, allowing for a personalised approach.

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