Synergistic inhibition of MEK and reciprocal feedback networks for targeted intervention in malignancy

The RAS-RAF-MEK-ERK signaling pathway (MAPK signaling pathway) plays a significant role in multiple pathological behaviorsand is most frequently dysregulated in more than 30% of human cancers. As key elements in this pathway, MEK1/2 play crucialroles in tumorigenesis and the inhibition of apoptosis, which makes their inhibition an attractive antitumor strategy. Dozens ofpotent non-ATP-competitive allosteric MEK1/2 inhibitors have been developed that have produced substantial improvement inclinical outcomes over the past decade. However, the efficacy of these agents is limited, and response rates are variable in a widerange of tumors that harbor RAS and RAF mutations due to the development of resistance, which is derived mainly from thepersistence of MAPK signaling and increased activation of the mutual feedback networks. Both intrinsic and acquired resistance toMEK inhibitors necessitates the synergistic targeting of both pathways to restore the therapeutic effects of a single agent. In thisreview, the significant role of the MAPK pathway in carcinogenesis and its therapeutic potential are comprehensively examinedwith a focus on MEK inhibitors. Then, the activation of feedback networks accompanying MEK inhibition is briefly reviewed.Combination strategies that involve the simultaneous inhibition of the original and resistance pathways are highlighted andelaborately described on the basis of the latest research progress. Finally, the obstacles to the development of MEK-relatedcombination systems are discussed in order to lay the groundwork for their clinical application as frontline treatments forindividual patients with MAPK-hyperactivated malignancies. Cite this article as: Li Y, Dong Q, Cui Y. Synergistic inhibition of MEK andreciprocal feedback networks for targeted intervention in malignancy. CancerBiol Med. 2019; 16: 415-34. doi: 10.20892/j.issn.2095-3941.2019.0137