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WCCS/EADO 2016 | Blocking C-MET and BRAF pathways in melanoma to overcome resistance in mouse models

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Clemens Krepler

Clemens Krepler, MD of the Wistar Institute, Philadelphia, PA, discusses resistance mechanisms in BRAF-mutated melanoma in mouse models. The tumors develop a very strong growth signal through the BRAF mutation, as it activates one of the main proliferation pathways. When the drug is administered, the proliferative pathway becomes blocked and the tumor finds a way around it. One way around is via C-MET, which is the receptor for HGF, which is also an important receptor in the liver cells, and is hijacked by the melanoma cells. He explains that he has found that before the patient received the BRAF inhibitor, they already had some cells that had high expression of the C-MET receptor. Following a few months of therapy, all the cells that were left over had high expression of this receptor, meaning the resistance population was already present. Based on this, a C-MET inhibitor was combined with an inhibitor of BRAF to block both pathways; this combination killed off the tumor cells in the mouse models. However, he believes that in patients, the tumor cells may find alternative routes and resistance would develop, but blocking C-MET would be successful in buying extra time.
Recorded at the 2016 World Congress on Cancers of the Skin (WCCS) and the Congress of the European Association of Dermato-Oncology (EADO) in Vienna, Austria.

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