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  • Review Article
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Targeting the mitogen-activated protein kinase cascade to treat cancer

Nature Reviews Cancer volume 4, pages 937–947 (2004)Cite this article

Key Points

  • The mitogen-activated protein kinase (MAPK) pathway controls the growth and survival of a broad spectrum of human tumours.

  • Activating mutations in RAS and RAF result in activation of the MAPK pathway and are present in a large percentage of solid tumours.

  • The central role of RAF and MAPK kinase (MEK) in transmitting signals through the RAS–MAPK pathway make these kinases promising targets of anticancer drugs.

  • MEK inhibitors are the first highly selective inhibitors of the MAPK pathway to enter the clinic.

  • Emerging clinical data show promising hints that suppression of the MAPK pathway can be achieved without unacceptable toxicity levels.

Abstract

The RAS–mitogen activated protein kinase (MAPK) signalling pathway has long been viewed as an attractive pathway for anticancer therapies, based on its central role in regulating the growth and survival of cells from a broad spectrum of human tumours. Small-molecule inhibitors designed to target various steps of this pathway have entered clinical trials. What have we recently learned about their safety and effectiveness? Will the MAPK pathway prove amenable to therapeutic intervention?

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Figure 1: The mitogen-activated protein kinase signalling pathway.
Figure 2: Downstream effects of extracellular signal-regulated kinase activation.

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Acknowledgements

We gratefully acknowledge J. Ohren for providing the structural diagrams and for his helpful comments.

Author information

Authors and Affiliations

  1. Molecular Sciences and Technologies, Pfizer Global Research and Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, 48105, Michigan, USA

    Judith S. Sebolt-Leopold & Roman Herrera

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  1. Judith S. Sebolt-Leopold
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  2. Roman Herrera
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Corresponding author

Correspondence to Judith S. Sebolt-Leopold.

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Competing interests

Both authors are employed by Pfizer Global Research and Development. Pfizer is widely known to have an active interest in the clinial development of MEK inhibitors — a subject that is included in this review.

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DATABASES

Entrez Gene

AKT

ARAF

BAD

BRAF

RAF1

cyclin D1

cyclin E

ERK1

ERK2

FOS

HDJ2

JUN

KRAS

MEK1

MEK2

MKP1

MYC

p21

p27

RSK

RAF

RHEB

RHOB

RND

SOS

VEGF

National Cancer Institute

breast cancer

colorectal cancer

leukaemias

multiple myeloma

non-small-cell lung cancer

ovarian cancer

pancreatic cancer

prostate cancer

renal-cell cancer

thyroid cancer

Glossary

ISOPRENOID

A 15-carbon farnesyl lipid modification required for membrane localization and activity of RAS and other signalling proteins.

IC50

The concentration of a drug required to inhibit target activity by 50%.

NON-COMPETITIVE INHIBITOR

A kinase inhibitor that does not bind to or interfere with the ATP-binding site of an enzyme.

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Sebolt-Leopold, J., Herrera, R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 4, 937–947 (2004). https://doi.org/10.1038/nrc1503

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  • DOI: https://doi.org/10.1038/nrc1503

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