Elucidating distinct roles for NF1 in melanomagenesis
Menée in vitro, in vivo et à partir d'échantillons tumoraux prélevés sur des patients atteints d'un mélanome métastatique, cette étude analyse le rôle joué par des mutations du gène suppresseur de tumeurs Nf1, en coopération avec des mutations du gène BRAF, dans la mélanogenèse et l'apparition d'une résistance thérapeutique
BRAF mutations play a well-established role in melanomagenesis; however, without additional genetic alterations tumor development is restricted by oncogene-induced senescence (OIS). Here we show that mutations in the NF1 tumor suppressor gene cooperate with BRAF mutations in melanomagenesis by preventing OIS. In a genetically engineered mouse model, Nf1 mutations suppress Braf-induced senescence, promote melanocyte hyperproliferation, and enhance melanoma development. Nf1 mutations function by deregulating both PI3K and ERK pathways. As such, Nf1/Braf mutant tumors are resistant to BRAF inhibitors but are sensitive to combined MEK/mTOR inhibition. Importantly, NF1 is mutated or suppressed in human melanomas that harbor concurrent BRAF mutations, NF1 ablation decreases the sensitivity of melanoma cell lines to BRAF inhibitors, and NF1 is lost in tumors from patients following treatment with these agents. Collectively, these studies provide mechanistic insight into how NF1 cooperates with BRAF mutations in melanoma and demonstrate that NF1-inactivation may impact responses to targeted therapies.
Cancer Discovery 2012