An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential
Menée à l'aide d'un modèle murin de mélanome résistant aux inhibiteurs de BRAF et sur des patients atteints d'un mélanome de stade avancé résistant aux inhibiteurs de BRAF et de MEK, cette étude met en évidence l'intérêt d'une stratégie thérapeutique visant à exploiter une caractéristique de ce type de tumeur
BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance that is frequently caused by reactivation of the mitogen activated protein kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor vorinostat suppresses SLC7A11, leading to a lethal increase in the already-elevated levels of ROS in drug-resistant cells. This causes selective apoptotic death of only the drug-resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with vorinostat in mice results in dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor-resistant melanoma, we find that vorinostat can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here.
Cell 2018