Abstract
Background Therapy of advanced melanoma has been improved with the advent of BRAF inhibitors. However, a limitation to such treatment is the occurrence of resistance. Several mechanisms have been implied in the development of resistance, which in most cases lead to downstream MEK reactivation. In order to overcome resistance MEK inhibitors are being clinically developed with promising results. However, also in this case resistance inevitably occurs. It is commonly believed that the establishment of resistance is facilitated by adaptive changes that take place in cancer cells shortly after exposure to kinase inhibitors. Our laboratory is interested in the identification of these early adaptive changes with the intent to discover additional targets for therapeutic intervention. Methods
Highlights
Therapy of advanced melanoma has been improved with the advent of BRAF inhibitors
We show that ErbB3 is the main RTK rapidly hyperphosphorylated in response to BRAF or MEK inhibition in melanoma cell lines harboring a variety of V600 BRAF mutations
ErbB3 activation, which is caused by increased autocrine production of neuregulin, can be fully abrogated by two distinct anti-ErbB3 monoclonal antibodies, A3 and A4. Most importantly these two mAbs individually or in combination strongly enhance the ability of different BRAF/MEK inhibitors to silence the oncogenic MAPK and AKT pathways
Summary
Therapy of advanced melanoma has been improved with the advent of BRAF inhibitors. A limitation to such treatment is the occurrence of resistance. Several mechanisms have been implied in the development of resistance, which in most cases lead to downstream MEK reactivation. In order to overcome resistance MEK inhibitors are being clinically developed with promising results. It is commonly believed that the establishment of resistance is facilitated by adaptive changes that take place in cancer cells shortly after exposure to kinase inhibitors. Our laboratory is interested in the identification of these early adaptive changes with the intent to discover additional targets for therapeutic intervention
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