Oral communication, PS6 / C73

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

A novel link between TGFbeta and MAP kinase signalling is involved in resistance to MEK inhibition in melanoma

The MAP-kinase pathway consisting of RAF, MEK and ERK is deregulated in over 90% of melanoma skin cancers. Last year a novel inhibitor (PLX4032) targeting the oncogenic RAF kinase V600E-BRAF in melanoma patients demonstrated an unprecedented 80% anti-tumour response. However, acquired resistance occurs rapidly through various and partially unknown mechanisms. Moreover due to the complex molecular mechanisms of RAF-kinase regulation, BRAF selective inhibitors can cause tumour-promoting effects in non-mutant BRAF patients. Therefore, targeting BRAF downstream effectors i.e. the kinase MEK can provide a more potent and specific way of treating melanoma. In addition, this also allows treating patients with NRAS mutations, which are found in up to 20% of melanomas and lead to MEK activation. Potent inhibitors of MEK are currently tested in the clinic and show promising results. However, recent findings demonstrate the existence of mechanisms that can also provide resistance against MEK inhibition. In summary, there is need for a better understanding of the mechanisms underlying resistance to MAP-kinase pathway inhibition. With this knowledge we can identify other ‘druggable’ proteins that can be targeted in combination with MAP-kinase pathway inhibitors. We have discovered a novel mechanism of resistance to MAP-kinase pathway inhibition involving a link between the BRAF/MEK/ERK cascade and TGFbeta signalling. The analysis of the regulatory link between TGFbeta and MAPkinase signalling revealed the involvement of the SMAD specific E3-ligase SMURF1. Exploiting the cross-talk between SMURF1 and the MAP-kinase-kinase MEK, we have identified a synthetic lethal approach that efficiently kills melanoma cells, thereby overcoming resistance. Acquired resistance to mono-therapy targeting the MAP-kinase pathway in melanoma is an increasingly apparent dilemma. However, our findings open new avenues for the treatment of melanoma based on combining agents with synergistic activity on the MAP-kinase pathway in order to prevent the development of resistance.

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