Oral Presentation 25th Lorne Cancer Conference 2013

BRAF and RAS signalling in melanoma: basic biology to clinical exploitation. (#2)

Richard Marais 1
  1. Paterson Institute for Cancer Research , , United Kingdom

The serine-threonine specific protein kinase BRAF is mutated in ~45% of melanomas and its upstream activator, the small G-protein NRAS is mutated in a further ~20% of cases.  We have developed mouse models of melanoma driven by oncogenic BRAF and oncogenic RAS.  When expressed in mature melanocytes, oncogenic BRAF induced melanoma with a median latency of about 12 months, indicating that mutant BRAF can be an initiating event in melanoma, but that by itself it is not sufficient.  Curiously, when expressed in embryonic mouse melanocytes, oncogenic BRAF was embryonically lethal.  In contrast to oncogenic BRAF, when oncogenic NRAS was expressed in adult melanocytes it did not induce melanoma, but when expressed in embryonic mouse melanocytes it induced melanomas of the brain that bore the cardinal features of leptomeningeal melanocytosis in children.  

The development of drugs that target the BRAF pathway has led to a paradigm shift in the clinical management of melanoma.  However, despite the impressive responses of patients to BRAF pathway targeting drugs, most patients eventually fail on treatment due to the development of resistance (acquired resistance), and about 20% of patients do not respond to these drugs despite the presence of a BRAF mutation (intrinsic resistance).  We have found that one of the mechanisms of BRAF resistance is upregulation of EGF receptor (EGFR) signalling.  This occurs due to upregulation of EGFR itself, increased production of EGF, downregulation of the EGFR negative regulator MIG6 and activation of SRC-STAT3 signalling.  Drugs that inhibit EGFR cooperate with BRAF drugs to block the growth of the resistant tumours and drugs that inhibit SRC work as monotherapy in these tumours.  These data highlight the importance of improved knowledge of melanoma biology to provide effective first-line and second-line therapies for melanoma patients.