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

Yanan Li; Qingrong Dong; Yukun Cui

doi:10.20892/j.issn.2095-3941.2019.0137

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

Cancer Biol Med. 2019 Aug;16(3):415-434. doi: 10.20892/j.issn.2095-3941.2019.0137.

Authors

Yanan Li^{1

2}, Qingrong Dong¹, Yukun Cui²

Affiliations

¹ Department of Radiology, First Clinical Medical College, Shanxi Medical University, Taiyuan 030001, China.
² Guangdong Provincial Key Laboratory of Breast Cancer Diagnosis and Treatment, Shantou University Medical College Cancer Hospital, Shantou 515041, China.

PMID: 31565475
PMCID: PMC6743629
DOI: 10.20892/j.issn.2095-3941.2019.0137

Abstract

The RAS-RAF-MEK-ERK signaling pathway (MAPK signaling pathway) plays a significant role in multiple pathological behaviors and is most frequently dysregulated in more than 30% of human cancers. As key elements in this pathway, MEK1/2 play crucial roles in tumorigenesis and the inhibition of apoptosis, which makes their inhibition an attractive antitumor strategy. Dozens of potent non-ATP-competitive allosteric MEK1/2 inhibitors have been developed that have produced substantial improvement in clinical outcomes over the past decade. However, the efficacy of these agents is limited, and response rates are variable in a wide range of tumors that harbor RAS and RAF mutations due to the development of resistance, which is derived mainly from the persistence of MAPK signaling and increased activation of the mutual feedback networks. Both intrinsic and acquired resistance to MEK inhibitors necessitates the synergistic targeting of both pathways to restore the therapeutic effects of a single agent. In this review, the significant role of the MAPK pathway in carcinogenesis and its therapeutic potential are comprehensively examined with 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 and elaborately described on the basis of the latest research progress. Finally, the obstacles to the development of MEK-related combination systems are discussed in order to lay the groundwork for their clinical application as frontline treatments for individual patients with MAPK-hyperactivated malignancies.

Keywords: MAPK signaling pathway; MEK inhibitor; combination therapy; malignancy; reciprocal feedback networks.