69IN - New molecular targets in melanoma

Date 01 October 2012
Event ESMO Congress 2012
Session Melanoma therapy: From frustration to enthusiasm
Topics Melanoma and other Skin Tumours
Pathology/Molecular Biology
Presenter Richard Marais
Authors R. Marais
  • Paterson Institute for Cancer Research, Director, M20 4BX - Manchester/UK

Abstract

Recent years have seen dramatic advances in the development of targeted and immunological therapeutics for melanoma. In the area of targeted therapy, the development of BRAF inhibitors has led to new paradigms of melanoma treatment, because BRAF drugs such as vemurafenib and dabrafinib can achieve objective responses in BRAF mutant melanoma patients. However, these responses are generally short-lived, and relapse may be inevitable. Notably, BRAF inhibitors drive an unexpected paradox: while they inhibit RAF signalling in cells expressing mutant BRAF, they activate RAF signalling in cells expressing oncogenic or activated RAS. This is because these inhibitors drive the formation of homo and hetero-dimers between BRAF and the closely related protein CRAF. The activation of this paradox appear, at least in some instances to underlie the mechanisms of resistance, and they also drive one of the curious side-effects of these drugs, the induction of non-melanoma neoplasms in the skin. Critically, it appears that upon activation of the paradox, the tumour cells can switch from being sensitive to the drug to being addicted to it. This creates an unexpected complication when managing these patients, but shows how improving our knowledge of the processes that drive tumourigenesis is critical to developing novel therapeutic strategies for cancer patients.

Disclosure

I have received an honourarium from Roche. I have consulted (unpaid) for novartis; I have consulted (unpaid) for Genentec.