Melanocytes are specialised pigment cells that are found in the skin, the eyes, the ears, the lining of the mouth and the brain. The melanocytes of the skin determine hair colour and skin tone, but more importantly, they provide protection from the damaging effects of ultraviolet (UV) radiation. Melanocytes are the precursors of melanoma, a potentially deadly form of skin cancer that affects over 12,000 people each year in the UK, killing over 2,000 people. In part, this high mortality is because melanoma cells are highly metastatic and spread to other parts of the body even in the early stages of the disease. Thus, early diagnosis and surgical removal of the primary lesion are essential if treatment is to be effective, because patients who develop the malignant metastatic form of the disease have very poor prognosis.
Over the last decade, we have made great strides into understanding the biology of melanoma. The BRAF gene is mutated in about half of melanoma cases, and the NRAS gene is mutated in about 20% of cases. These proteins are part of a conserved signalling pathway that regulates cell proliferation and survival, and the mutant proteins drive uncontrolled cell growth and tumour progression.
Our laboratory focuses on melanoma biology and we use a combination of approaches, including biochemistry, cell and molecular biology, structural biology, transgenic models and next generation signalling. Following the discovery in 2002 that BRAF is mutated in melanoma we validated BRAF as a therapeutic target and demonstrated that it is an oncogene that can transform immortalised melanocytes. We further demonstrated that oncogenic BRAF could be a founder mutation in melanomagenesis, but that it was not enough by itself and that other genetic events were required. We demonstrated a complex relationship between RAS/RAF and cAMP signalling in melanoma cells and demonstrated that cGMP regulates BRAF mutant melanoma cell migration.
A key aim is to translate our basic research findings into patient benefit. In collaboration with Professor David Barford (ICR, London), we solved the crystal structure of the BRAF kinase domain. This taught us how BRAF is regulated and we used that information to perform a BRAF drug discovery programme in collaboration with Professor Caroline Springer (ICR, London). Critically, we found that while BRAF drugs inhibit cell signalling in melanoma cells carrying mutations in BRAF, they activate cell signalling in cells that carry mutations in NRAS. This paradox occurs because BRAF drugs drive the formation of hetero and homo-dimers between BRAF and a closely related family member called CRAF. This drives CRAF and downstream pathway hyper-activation and in some situations tumourigensis. In particular, we have shown that this paradox can drive the formation of non-melanoma skin lesions in patients treated with BRAF inhibitors and have also shown that it can drive cell survival in drug-resistant chronic myeloid leukaemia.
We are continuing to work to increase our knowledge of BRAF and NRAS biology in melanoma. We are using next generation sequencing to unravel the genes that cooperate with BRAF to drive tumourigenesis. We are also investigating how environmental insults induce melanoma and how BRAF signalling alters melanoma cell metabolism. We are participating in clinical trials and are working to understand mechanisms of resistance to targeted therapies in melanoma patients. We also continue to collaborate with Professor Springer, this time to develop drugs against Lysyl Oxidase, an enzyme that drives metastasis.