Allele-specific mechanisms of activation of MEK1 mutants determine their properties
Menée sur des lignées cellulaires cancéreuses et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, en fonction de diverses mutations affectant le gène MEK1, son activation favorise la prolifération cellulaire
Mutations at multiple sites in MEK1 occur in cancer suggesting that their mechanisms of activation might be different. We analyzed 17 tumor-associated MEK1 mutants and found that they drove ERK signaling autonomously or in a RAS-RAF dependent manner. The latter are sensitive to feedback inhibition of RAF, which limits their functional output and often co-occur with RAS or RAF mutations. They act as amplifiers of RAF signaling. By contrast, another class of mutants delete a hitherto unrecognized negative regulatory segment of MEK1, is RAF- and phosphorylation-independent, unaffected by feedback inhibition of upstream signaling, and drives high ERK output and transformation in the absence of RAF activity. Moreover, these RAF-independent mutants are insensitive to allosteric MEK inhibitors which bind to the inactivated form of MEK1. All the mutants were sensitive to an ATP-competitive MEK inhibitor. Thus, our study comprises a novel therapeutic strategy for tumors driven by RAF-independent MEK1 mutants.
Cancer Discovery 2018