The clinical development of MEK inhibitors

Yujie Zhao, Alex Adjei

Research output: Contribution to journalReview article

188 Citations (Scopus)

Abstract

Aberrant activation of the RAS-RAF-MEK-ERK1/2 pathway occurs in more than 30% of human cancers. As part of this pathway, MEK1 and MEK2 have crucial roles in tumorigenesis, cell proliferation and inhibition of apoptosis and, therefore, MEK1/2 inhibition is an attractive therapeutic strategy in a number of cancers. Highly selective and potent non-ATP-competitive allosteric MEK1/2 inhibitors have been developed and assessed in numerous clinical studies over the past decade. These agents are not efficacious in a broad range of unselected cancers, although single-agent antitumour activity has been detected mainly in tumours that harbour mutations in genes encoding the members of the RAS and RAF protein families, such as certain melanomas. Combinations of MEK1/2 inhibitors and cytotoxic chemotherapy, and/or other targeted agents are being studied to expand the efficacy of this class of agents. Identifying predictive biomarkers, and delineating de novo and acquired resistance mechanisms are essential for the future clinical development of MEK inhibitors. We discuss the clinical experience with MEK inhibitors to date, and consider the novel approaches to MEK-inhibitor therapy that might improve outcomes and lead to the wider use of such treatments.

Original languageEnglish (US)
Pages (from-to)385-400
Number of pages16
JournalNature Reviews Clinical Oncology
Volume11
Issue number7
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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Mitogen-Activated Protein Kinase Kinases
Neoplasms
MAP Kinase Signaling System
Antineoplastic Agents
Melanoma
Carcinogenesis
Therapeutics
Biomarkers
Cell Proliferation
Apoptosis
Drug Therapy
Mutation
Genes
Proteins

ASJC Scopus subject areas

  • Oncology

Cite this

The clinical development of MEK inhibitors. / Zhao, Yujie; Adjei, Alex.

In: Nature Reviews Clinical Oncology, Vol. 11, No. 7, 01.01.2014, p. 385-400.

Research output: Contribution to journalReview article

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