The mitogen-activated protein kinases (MAPKs) mediate intracellular signals activated by a wide variety of extracellular stimuli. These serine/threonine kinase are activated by MEK 1/2, MEK3/6, MEK4/7 and MEK5, respectively. The RAS-RAF-MEK1/2 pathway is commonly activated by various extracellular stimuli, growth factors, hormones, cytokines and environmental stresses, leading to distinct intracellular responses via either a series of phosphorylation events and of protein-protein interactions involving RAS, RAF, ERK and MEK. The activation of the RAS-RAF-MEK-MAPK pathway culminates in the regulation of gene transcription promoting cancer cell proliferation, survival, migration and angiogenesis. Genes encoding RAS or BRAF, when mutated or amplified, activate MAPK signalling through MEK, making MEK an attractive target for anti-cancer drug development. Whereas MEK is not frequently found mutated in solid tumours, BRAF is mutated in about 20% of all cancers and in approximately 40 to 60% of melanomas; furthermore, KRAS or NRAS mutations have been found in about 55% of metastatic CRC (mCRC). Lower rate of BRAF mutations have been observed in lung cancer (2-4%) whereas KRAS mutations remain the most frequent alteration in lung cancer, with an average mutation rate of 20-30% in adenocarcinoma. MEK1/2 act as a transducer of the growth factor receptorRAS-RAF-MAPK signalling cascade and its role in cancer development and progression in selected human cancers, such as NSCLC and CRC.

References

1.Martinelli E, et al. Cancer Treat Rev. 2017;53:61–69.