Introduction: The MAPK pathway is essential for regulation of cellular proliferation, differentiation and survival. Multiple human cancers have demonstrated activation of Raf-mitogen-Activated kinase kinase (MEK)-extracellular signal-related kinase signaling, a hallmark of these tumors. Efforts to inhibit various protein kinases in this pathway have led to the development of MEK inhibitors. Selumetinib is one such drug, functioning as an oral, selective non-ATP-competitive MEK1/2 inhibitor.
Areas covered: In this article, the authors discuss the underlying biology of MEK inhibition and its rationale in cancer treatment. Furthermore, the authors summarize the clinical development of selumetinib in various tumor types, from initial Phase I studies to randomized Phase II studies, both as monotherapy or in combination with other chemotherapeutics.
Expert opinion: Given the frequency of activated MAPK signaling in multiple tumor types, the potent MEK inhibitor selumetinib had strong preclinical and early clinical rationale, particularly in those tumors harboring KRAS or BRAF mutations. While efficacy signals have been seen in various tumor types treated with selumetinib, better biomarkers are needed to select patients most likely to respond favorably to this agent. Furthermore, combinatorial therapy with selumetinib and other targeted agents can likely be optimized to maximize the antitumor effect of inhibiting RAS/MAPK signaling.
- Extracellular signal-related kinase
- Mitogen-Activated protein kinase
ASJC Scopus subject areas
- Pharmacology (medical)