Developments of MEK inhibitors as future cancer therapies: what have we learned from preclinical and clinical studies?

Introduction: The combination of MEK and BRAF inhibitors is effective in melanomas and other tumors with BRAF V600E mutations. MEK inhibitors enhance efficacy and delay the development of resistance to BRAF inhibitors. Recently, MEK inhibitors have demonstrated activity in plexiform neurofibromas in patients with type 1 neurofibromatosis and in histiocytic neoplasms. In the preclinical setting, MEK inhibitors are effective in tumors with RAS or receptor tyrosine kinase mutations. However, after the inhibition of MEK, regulatory feedback determines the rebound activation of ERK, thereby limiting the effect of the MEK blockade. In early clinical trials, MEK inhibitor monotherapy has shown limited efficacy in RAS-mutated tumors, whereas trials combining MEK and RAS inhibitors are still ongoing. Areas covered: Clinical trials have been selected from clinicaltrials.gov searching for ‘MEK inhibitors,’ and their results have been searched in PubMed and meeting abstracts. Preclinical studies have been searched in PubMed using the names of the MEK inhibitors. This is a descriptive review. Expert opinion: While MEK inhibitors in combination with BRAF inhibitors obtained one of the first tumor-agnostic FDA approvals for BRAF V600E/K mutated tumors, additional indications for MEK inhibitors alone have been received in very selected diseases for which molecular characterization is crucial.