Master of Science [M.Sc] [Neuromusculoskeletal Physiotherapy] From University of Brighton

Mutation of BRAF is present in 30-70% of melanoma; the most common mutation, V600E, results in activation of the MAPK/ERK signalling pathway driving tumourigenesis and resistance to apoptosis. The development of vemurafenib (approved for clinical use in 2011) has proved a breakthrough in the treatment of advanced melanoma. However, 20-50% of melanomas with V600E do not respond to treatment. In those that do, the duration of response is limited by acquired resistance through multiple mechanisms.

Abnormal expression and activity of the ?3 integrins, ?IIb?3 and ?v?3, in tumour cells is strongly associated with melanoma progression and metastasis. ?3 integrin expression promotes cell survival, migration, and metastasis via the lymph system and bloodstream by enhancing invasion and extravasation of the primary tumour, supporting tumour platelet interactions, and cell adhesion, proliferation and tumour angiogenesis at the metastatic sites. Such interactions have recently been identified as important contributors to anticancer drug resistance, but the role of integrins in resistance to BRAFV600E inhibition is currently unexplored. This project will investigate the role of integrin-ECM interaction in resistance to BRAFV600E targeted therapy, and the effect of co-targeting integrin and BRAFV600E mediated signalling, which should provide information important for the planning of future combination therapies for advanced melanoma.