The role of tumour microenvironment interactions in melanoma therapy resistance

The incidence of malignant melanoma has steadily increased over the past 30 years, and it is predicted that 76,250 new cases will be diagnosed in the US and over 10,000 in the UK this year. Advanced melanoma is the most deadly form of skin cancer, with average survival of 8-18 months. 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 β3 integrins, αIIbβ3 and αvβ3, in tumour cells is strongly associated with melanoma progression and metastasis. β3 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.

This will involve using cell-based techniques to:
1. Characterise integrin expression, activity, and signalling pathways active in melanoma cells with a range of known kinase mutations and resistant/sensitive phenotypes.
2. Characterise changes in integrin expression, activity and signalling pathways in response to exposure to BRAFV600E selective inhibitors.
3. Investigate the effect of integrin ligation on cellular response to BRAFV600E selective inhibitors.
4. Investigate in vitro response to BRAFV600E selective inhibitors in combination with an integrin antagonist selected to act on the integrin pathways identified as contributing to cell survival and drug resistance