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The Biology and Clinical Development of MEK Inhibitors for Cancer

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Abstract

The mitogen-activated protein kinase kinases (MAPKK) MEK1 and MEK2 are integral members of the MAPK/ERK signaling pathway and are of interest in the development of anti-cancer therapeutics. The MAPK/ERK pathway is dysregulated in more than 30 % of cancers, predominately by mutations in RAS and BRAF proteins, and MEK serves as a potential downstream target for both of these. The biology of MEK inhibition is complex, as the molecule is differentially regulated by upstream RAS or RAF. This has impacted on the past development of MEK inhibitors as treatments for cancer and may be exploited in more rational, molecularly selected drug development plans in the future. The role of MEK in cancer and the mechanism of action of MEK inhibitors is reviewed. Furthermore, MEK inhibitors that are available in standard practice, as well as those most advanced in clinical development, are discussed. Finally, next steps in the development of MEK inhibitors are considered.

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Disclosures

Jason J. Luke has acted as a paid consultant to Bayer and Genentech and has received clinical trial support to institution from EMD Serono, GlaxoSmithKline, and Novartis for MEK inhibitor-based studies. Patrick A. Ott has no relevant disclosures. Geoffrey I. Shapiro has received clinical trial support to institution from Pfizer, GlaxoSmithKline, and Genentech for MEK inhibitor-based studies. No specific funding was received for this manuscript.

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Authors and Affiliations

  1. Melanoma and Developmental Therapeutics Clinics, University of Chicago Cancer Center, University of Chicago, 5841 S. Maryland Ave., MC2115, Chicago, IL, 60637, USA

    Jason J. Luke

  2. Department of Medical Oncology, Early Drug Development Center, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA

    Geoffrey I. Shapiro

  3. Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 450 Brookline Ave., Boston, MA, 02215, USA

    Patrick A. Ott & Geoffrey I. Shapiro

  4. Department of Medical Oncology, Center for Melanoma Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA

    Patrick A. Ott

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  1. Jason J. Luke
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Correspondence to Jason J. Luke.

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Luke, J.J., Ott, P.A. & Shapiro, G.I. The Biology and Clinical Development of MEK Inhibitors for Cancer. Drugs 74, 2111–2128 (2014). https://doi.org/10.1007/s40265-014-0315-4

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