The biology and clinical exploitation of BRAF and RAS signalling in cancer


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Richard Marais1
1The Cancer Reserch UK Manchester Institute, Manchester, UK

Abstract

The protein kinase BRAF is mutated in about half of melanomas and its upstream activator, NRAS, is mutated in a further 20% of cases. To investigate the role of these proteins in melanomagenesis, we have developed mouse models of melanoma driven by V600EBRAF and G12DNRAS. Notably, when V600EBRAF is expressed in the melanocytes of mature mice, it induces BRAF in about 70% of the animals with a median latency of ~12 months. This shows that BRAF can be a founder mutation in melanoma, but the long latency suggests that other genetic events are required to cooperate with BRAF to drive melanomagenesis and we are currently examining gene-gene and gene-environmental relationships in this model to identify these additional events.

In contrast to V600EBRAF, G12DNRAS does not induce melanoma when expressed in adult mouse melanocytes. However, when expressed in the melanocytes of embryonic mice G12DNRAS induces leptomeningeal melanocytosis that presents the cardinal features of this rare disease in children, a condition that also appears to be driven by oncogenic RAS. We are currently investigating why congenital expression of oncogenic NRAS predisposes children to melanoma of the CNS.

Finally, BRAF has been validated as a therapeutic target in melanoma, but responses to BRAF drugs are limited and most patients will develop resistance after a relatively short period in remission. To investigate mechanisms of resistance, we are developing patient-derived xenografts from melanoma patients treated with targeted agents. These tumours will be fully characterised using next generation sequencing, proteomics and molecular pathology to allow us to determine mechanisms of resistance and establish a platform of precision medicine that will improve outcomes for melanoma patients.