Allele-specific mechanisms of activation of MEK1 mutants determine their properties [Research Articles]

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.

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