Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Targeting the mitogen-activated protein kinase cascade to treat cancer

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?

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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

Similar content being viewed by others

References

  1. Hahn, W. C. & Weinberg, R. A. Modelling the molecular circuitry of cancer. Nature Rev. Cancer 411, 331–341 (2002).

    Article  CAS  Google Scholar 

  2. Evan, G. I. & Vousden, K. H. Proliferation, cell cycle and apoptosis in cancer. Nature 411, 342–348 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Grossmann, J. Molecular mechanisms of 'detachment-induced apoptosis – anoikis'. Apoptosis 7, 247–260 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Nelson, W. J. & Nusse, R. Convergence of Wnt, β-catenin, and cadherin pathways. Science 303, 1483–1487 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Assoian, R. K. Anchorage-dependent cell cycle progression. J. Cell Biol. 136, 1–4 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Roovers, K. & Assoian, R. K. Integrating the MAP kinase signal into the G1 phase cell cycle machinery. Bioessays 22, 818–826 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Meloche, S., Seuwen, K., Pages, G. & Pouyssegur, J. Biphasic and synergistic activation of p44mapk (ERK1) by growth factors: correlation between late phase activation and mitogenicity. Mol. Endocrinol. 6, 845–854 (1992).

    CAS  PubMed  Google Scholar 

  8. Pages, G. et al. Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. Proc. Natl Acad. Sci. USA 90, 8319–8323 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J. & Saltiel, A. R. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc. Natl Acad. Sci. USA 92, 7686–7689 (1995). The first report of a small-molecule MEK inhibitor, PD098059. Findings with this compound have subsequently been reported in over 2,000 publications, documenting the central role of the MAPK pathway in a diverse array of physiological events, including tumour proliferation, differentiation, angiogenesis and survival.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Alessi, D. R., Cuenda, A., Cohen, P., Dudley, D. T. & Saltiel, A. R. PD098059 is a specific inhibitor of the activation of mitogen-activated protein kinase in vitro and in vivo. J. Biol. Chem. 270, 27489–27494 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Brondello, J. M., McKenzie, R. R., Sun, H., Tonks, N. K. & Pouyssegur, J. Constitutive MAP kinase phosphatase (MKP-1) expression blocks G1 specific gene transcription and S-phase entry in fibroblasts. Oncogene 10, 1895–1904 (1995).

    CAS  PubMed  Google Scholar 

  12. Lavoie, J. N., L'Allemain, G., Brunet, A., Muller, R. & Pouyssegur, J. Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J. Biol. Chem. 271, 20608–20616 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. Cheng, M., Sexl, V., Sherr, C. J. & Roussel, M. Assembly of cyclin D-dependent kinase and titration of p27kip1 regulated by mitogen-activated protein kinase kinase (MEK1). Proc. Natl Acad. Sci. USA 95, 1091–1096 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cook, S. J., Aziz, N. & McMahon, M. The repertoire of Fos and Jun proteins expressed during the G1 phase of the cell cycle is determined by the duration of mitogen-activated protein kinase activation. Mol. Cell. Biol. 19, 330–341 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Marshall, C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–185 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Raabe, T. & Rapp, U. R. Ras signaling: PP2A puts Ksr and Raf in the right place. Curr. Biol. 13, R635–R637 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Sewing, A., Wiseman, B., Lloyd, A. C. & Land, H. A high-intensity Raf signal causes cell cycle arrest mediated by p21Cip1. Mol. Cell. Biol. 17, 5588–5597 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pumiglia, K. M. & Decker, S. J. Cell cycle arrest mediated by the MEK/migogen-activated protein kinase pathway. Proc. Natl Acad. Sci. USA 94, 448–452 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang, B. H. et al. Serum- and glucocorticoid-inducible kinase SGK phosphorylate and negatively regulates B-Raf. J. Biol. Chem. 276, 31620–31626 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Guan, K. L. et al. Negative regulation of the serine/threonine kinase B-raf by Akt. J. Biol. Chem. 275, 27354–27359 (2000).

    CAS  PubMed  Google Scholar 

  21. Murphy, L. O., MacKeigan, J. P. & Blenis, J. A network of immediate early gene products propagates subtle differences in mitogen-activated protein kinase signal amplitude and duration. Mol. Cell. Biol. 24, 144–153 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Murphy, L. O., Smith, S., Chen, R. H., Fingar, D. C. & Blenis, J. Molecular interpretation of ERK signal duration by immediate early gene products. Nature Cell Biol. 4, 556–564 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Sherr, C. J. & Roberts, J. M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13, 1501–1512 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Bottazzi, M. E., Zhu, X., Bohmer, R. M. & Assoian, R. K. Regulation of p21cip1 expression by growth factors and the extracellular matrix reveals a role for transient ERK activity in G1 phase. J. Cell Biol. 146, 1255–1264 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Meloche, S. Cell cycle reentry of mammalian fibroblasts is accompanied by the sustained activation of p44mapk and p42mapk isoforms in the G1 phase and their inactivation at the G1/S transition. J. Cell Physiol. 163, 577–588 (1995).

    Article  CAS  PubMed  Google Scholar 

  26. Herrera, R. & Sebolt-Leopold, J. S. Unraveling the complexities of the Raf/MAP kinase pathway for pharmacological intervention. Trends Mol. Medicine 8, S27–S31 (2002).

    Article  CAS  Google Scholar 

  27. Chen, J. et al. Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK–ERK independent mechanism. Proc. Natl Acad. Sci. USA 98, 7783–7788 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shimamura, A. et al. Rsk 1 mediates a MEK–MAP kinase cell survival signal. Curr. Biol. 10, 127–135 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Bonni, A. et al. Cell survival promoted by the Ras–MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286, 1358–1362 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Baumann, B. et al. Raf induces NF-κB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation. Proc. Natl Acad. Sci. USA 97, 4615–4620 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Murakami, M. S. & Morrison, D. K. Raf-1 without MEK? Sci. STKE 99, PE30 (2001).

    Google Scholar 

  32. Ballif, B. A. & Blenis, J. Molecular mechanisms mediating mammalian mitogen-activated protein kinase (MAPK) kinase (MEK)–MAPK cell survival signals. Cell Growth Differ. 12, 397–408 (2001).

    CAS  PubMed  Google Scholar 

  33. Pages, G. et al. Defective thymocyte maturation in p44 MAP kinase (Erk1) knockout mice. Science 286, 1374–1377 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Giroux, S. et al. Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta. Curr. Biol. 9, 369–376 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Howe, A. K., Aplin, A. E. & Juliano, R. L. Anchorage-dependent ERK signaling – mechanisms and consequences. Curr. Opin. Genet. Dev. 12, 30–35 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Wada, T. & Penninger, J. M. Mitogen-activated protein kinases in apoptosis regulation. Oncogene 23, 2838–2849 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Platanias, L. C. MAP kinase signaling pathways and hematologic malignancies. Blood 101, 4667–4679 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Stanton, L. A., Underhill, T. M. & Beier, F. MAP kinases in chondrocyte differentiation. Dev. Biol. 263, 165–175 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Hofman, P. Molecular regulation of neutrophil apoptosis and potential targets for therapeutic strategy against the inflammatory process. Curr. Drug Targets. Inflamm. Allergy 3, 1–9 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Ji, R. R. Mitogen-activated protein kinases as potential targets for pain killers. Curr. Opin. Investig. Drugs 5, 71–75 (2004).

    PubMed  Google Scholar 

  41. Sugden, P. H. Signalling pathways in cardiac myocyte hypertrophy. Ann. Med. 33, 611–622 (2001).

    CAS  PubMed  Google Scholar 

  42. Barron, A. J., Finn, S. G. & Fuller, S. J. Chronic activation of extracellular-signal-regulated protein kinases by phenylephrine is required to elicit a hypertrophic response in cardiac myocytes. Biochem. J. 371, 71–79 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Downward, J. Targeting Ras signaling pathways in cancer therapy. Nature Rev. Cancer 3, 11–22 (2003).

    Article  CAS  Google Scholar 

  44. Sebti, S. M. & Der, C. J. Searching for the elusive targets of farnesyltransferase inhibitors. Nature Rev. Cancer 3, 945–951 (2003).

    Article  CAS  Google Scholar 

  45. Zhu, K., Hamilton, A. D. & Sebti, S. M. Farnesyltransferase inhibitors as anticancer agents: current status. Curr. Opin. Invest. Drugs 4, 1428–1435 (2003).

    CAS  Google Scholar 

  46. End, D. W. et al. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res. 61, 131–137 (2001).

    CAS  PubMed  Google Scholar 

  47. van Cutsem, E. et al. Phase III trial comparing gemcitabine + R115777 (Zarnestra) versus gemcitabine + placebo in advanced pancreatic cancer (PC). Proc. Am. Soc. Clin. Oncol. 21, A517 (2002).

    Google Scholar 

  48. Liu, A., Du, W., Liu, J. P., Jessell, T. M. & Prendergast, G. C. RhoB alteration is necessary for apoptotic and antineoplastic responses to farnesyltransferase inhibitors. Mol. Cell. Biol. 20, 6105–6113 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Katz, M. E. & McCormick, F. Signal transduction from multiple Ras effectors. Curr. Opin. Genet. Dev. 7, 75–79 (1997).

    Article  CAS  PubMed  Google Scholar 

  50. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002). Seminal discovery of somatic mutations of BRAF in human cancer. This report described the prevalence of BRAF mutations in melanoma and led to BRAF being viewed as a promising target for drug development for this patient population.

    Article  CAS  PubMed  Google Scholar 

  51. Satyamoorthy, K. et al. Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res. 63, 756–759 (2003).

    CAS  PubMed  Google Scholar 

  52. Rajagopalan, H. et al. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 418, 934 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Yuen, S. T. et al. Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res. 62, 6451–6455 (2002).

    CAS  PubMed  Google Scholar 

  54. Singer, G. et al. Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J. Natl Cancer Inst. 95, 484–486 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Cohen, Y. et al. BRAF mutation in papillary thyroid carcinoma. J. Natl Cancer Inst. 95, 625–627 (2003).

    Article  CAS  PubMed  Google Scholar 

  56. Kimura, E. T. et al. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC–RAS–BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res. 63, 1454–1457 (2003).

    CAS  PubMed  Google Scholar 

  57. Karasarides, M. et al. B-RAF is a therapeutic target in melanoma. Oncogene 23, 6292–6298 (2004). Reports the use of RNA interference to demonstrate that BRAF depletion impairs ERK signalling and proliferation in melanoma cells, unlike ARAF and RAF1 depletion. These findings strengthened the argument for developing a BRAF-targeted therapeutic agent against melanoma.

    Article  CAS  PubMed  Google Scholar 

  58. Tuveson, D. A., Weber, B. L. & Herlyn, M. BRAF as a potential therapeutic target in melanoma and other malignancies. Cancer Cell 4, 95–98 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Bollag, G., Freeman, S., Lyons, J. F. & Post, L. E. Raf pathway inhibitors in oncology. Curr. Opin. Invest. Drugs 4, 1436–1441 (2003).

    CAS  Google Scholar 

  60. Lee, J. T. & McCubrey, J. A. BAY-43-9006 Bayer/Onyx. Curr. Opin. Invest. Drugs. 4, 757–763 (2003).

    CAS  Google Scholar 

  61. Hotte, S. J. & Hirte, H. W. BAY 43-9006: early clinical data in patients with advanced solid malignancies. Curr. Pharm. Des. 8, 2249–2253 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. DeGrendele, H. Activity of the Raf kinase inhibitor BAY 43-9006 in patients with advanced solid tumors. Clin. Colorectal Cancer 3, 16–18 (2003).

    Article  CAS  Google Scholar 

  63. Verheul, H. M. & Pinedo, H. M. Vascular endothelial growth factor and its inhibitors. Drugs Today (Barc) 39 (Suppl. C), 81–93 (2003).

    CAS  Google Scholar 

  64. Hilger, R. A. et al. ERK1/2 phosphorylation: a biomarker analysis within a phase I study with the new Raf kinase inhibitor BAY 43-9006. Int. J. Clin. Pharmacol. Ther. 40, 567–568 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Chong, H., Vikis, H. G., Guan, K. L. Mechanisms of regulating the Raf kinase family. Cell Signal. 15, 463–469 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Mercer, K. E. & Pritchard, C. A. Raf proteins and cancer: B-Raf is identified as a mutational tartet. Biochim. Biophys. Acta 1653, 25–40 (2003).

    CAS  PubMed  Google Scholar 

  67. Wan, P. T. C. et al. Mechanism of activation of the RAF–ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116, 855–867 (2004). Describes the crystal structure of wild-type and oncogenic BRAF kinase domains. This important study provides insight into how BRAF is activated and how mutations in this protein lead to tumorigenesis.

    Article  CAS  PubMed  Google Scholar 

  68. Dibb, N. J., Dilworth, S. M. & Mol, C. D. Switching on kinases: oncogenic activation of BRAF and the PDGFR family. Nature Rev. Cancer 4, 718–727 (2004).

    Article  CAS  Google Scholar 

  69. Cowley, S., Paterson, H., Kemp, P. & Marshall, C. J. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH3T3 cells. Cell 77, 841–852 (1994).

    Article  CAS  PubMed  Google Scholar 

  70. Mansour, S. J. et al. Transformation of mammalian cells by constitutively active MAP kinase kinase. Science 265, 966–970 (1994). Although MEK is not an oncogene, this study showed that constitutively activated MEK possesses transforming activity, providing the impetus for targeting the MAPK pathway in the development of molecular-targeted drugs.

    Article  CAS  PubMed  Google Scholar 

  71. Hoshino, R. et al. Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 18, 813–822 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Haystead, T. A., Dent, P., Wu, J., Haystead, C. M. & Sturgill, T. W. Ordered phosphorylation of p42mapk by MAP kinase kinase. FEBS Lett. 306, 17–22 (1992).

    Article  CAS  PubMed  Google Scholar 

  73. Sebolt-Leopold, J. S. MEK inhibitors: a therapeutic approach to targeting the Ras–MAP kinase pathway in tumors. Curr. Pharmaceutical Design 10, 1907–1914 (2004).

    Article  CAS  Google Scholar 

  74. Favata, M. F. et al. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J. Biol. Chem. 273, 18623–18632 (1998).

    Article  CAS  PubMed  Google Scholar 

  75. Sebolt-Leopold, J. S. et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nature Med. 5, 81–816 (1999). The first report of a small-molecule MEK inhibitor having efficacy in tumour-bearing mice. Importantly, pharmacodynamic assays linked antitumour efficacy with suppression of the MAPK pathway.

    Article  CAS  Google Scholar 

  76. Allen, L. F., Sebolt-Leopold, J. S. & Meyer, M. CI-1040 (PD184352), a targeted signal transduction inhibitor of MEK (MAPKK). Semin. Oncol. 30, 105–116 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Rinehart, J. et al. Multicenter phase 2 study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon and pancreatic cancer. J. Clin. Oncol. 13 Oct 2004 (doi:10.1200/JCO.2004.01.185)

  78. Ohren, J. et al. Structures of human MAP Kinase Kinase 1 (MEK1) and MEK2 reveal a novel mode of non-competitive kinase inhibition. Nature Struct. Biol. (in the press). Structural evidence that both MEK1 and MEK2 possess a unique inhibitor-binding pocket adjacent to the ATP-binding site. This explains the high degree of selectivity observed with MEK inhibitors in clinical development.

  79. Bishop, A. C. A hot spot for protein kinase inhibitor sensitivity. Chem. Biol. 11, 587–591 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Tamborini, E. et al. A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology 127, 294–299 (2004).

    Article  CAS  PubMed  Google Scholar 

  81. Yeung, K. et al. Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein. Mol. Cell. Biol. 20, 3079–3085 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wang, Y. et al. The RAS effector RIN1 directly competes with RAF and is regulated by 14-3-3 proteins. Mol. Cell. Biol. 22, 916–926 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Matheny, S. A. et al. Ras regulates assembly of mitogenic signaling complexes through the effector protein IMP. Nature 427, 256–260 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Farooq, A. & Zhou, M. -M. Structure and regulation of MAPK phosphatases. Cell. Signalling 16, 769–779 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Shapiro, P. S. & Ahn, N. G. Feedback regulation of Raf-1 and mitogen-activated protein kinase (MAP) kinase kinases 1 and 2 by MAP kinase phosphatase-1 (MKP-1). J. Biol. Chem. 273, 1788–1793 (1998).

    Article  CAS  PubMed  Google Scholar 

  86. Guan, K. L. et al. Negative regulation of the serine/threonine kinase B-Raf by Akt. J. Biol. Chem. 275, 27354–27359 (2000).

    CAS  PubMed  Google Scholar 

  87. Zhang, B. H. et al. Serum- and glucocorticoid-inducible kinase SGK phosphorylates and negatively regulates B-Raf. J. Biol. Chem. 276, 31620–31626 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Sivaraman et al. Hyperexpression of mitogen-activated protein kinase in human breast cancer. J. Clin. Invest. 99, 1478–1483 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. El-Ashry et al. Constitutive Raf-1 kinase activity in breast cancer cells induces both estrogen-independent growth and apoptosis. Oncogene 15, 423–435 (1997).

    Article  CAS  PubMed  Google Scholar 

  90. Coutts A. S. & Murphy, L. C. Elevated mitogen-activated protein kinase activity in estrogen-nonresponsive human breast cancer cells. Cancer Res. 58, 4071–4074 (1998).

    CAS  PubMed  Google Scholar 

  91. Donovan, J. C., Milic, A. & Slingerland, J. M. Constitutive MEK/MAPK activation leads to p27Kip1 deregulation and antiestrogen resistance in human breast cancer cells. J. Biol. Chem. 276, 40888–40895 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Lee, S. H. et al. Colorectal tumors frequently express phosphorylated mitogen-activated protein kinase. APMIS 112, 233–238 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Wang, H. & Chakrabarty, S. Platelet-activating factor activates mitogen-activated protein kinases, inhibits proliferation, induces differentiation and suppresses the malignant phenotype of human colon carcinoma cells. Oncogene 22, 2186–2191 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Vial, E. & Marshall, C. J. Elevated ERK–MAP kinase activity protects the FOS family member FRA-1 against proteasomal degradation in colon carcinoma cells. J. Cell Sci. 116, 4957–4963 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Ishino, K. et al. Enhancement of anchorage-independent growth of human pancreatic carcinoma MIA PaCa-2 cells by signaling from protein kinase C to mitogen-activated protein kinase. Mol. Carcinog. 34, 180–186 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Tan, X. et al. Relationship between the expression of extracellular signal-regulated kinase 1/2 and the dissociation of pancreatic cancer cells: involvement of ERK1/2 in the dissociation status of cancer cells. Int. J. Oncol. 24, 815–820 (2004).

    CAS  PubMed  Google Scholar 

  97. Manzano, R. G. et al. CL100 expression is down-regulated in advanced epithelial ovarian cancer and its re-expression decreases its malignant potential. Oncogene 21, 4435–4447 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Gioeli, D., Mandell, J. W., Petroni, G. R., Frierson, H. F. Jr & Weber, M. J. Activation of mitogen-activated protein kinase associated with prostate cancer progression. Cancer Res. 59, 279–284 (1999).

    CAS  PubMed  Google Scholar 

  99. Bakin, R. E., Gioeli, D., Sikes, R. A., Bissonette, E. A. & Weber, M. J. Constitutive activation of the Ras/mitogen-activated protein kinase signaling pathway promotes androgen hypersensitivity in LNCaP prostate cancer cells. Cancer Res. 63, 1981–1989 (2003).

    CAS  PubMed  Google Scholar 

  100. Zayzafoon, M., Abdulkadir, S. A. & McDonald, J. M. Notch signaling and ERK activation are important for the osteomimetic properties of prostate cancer bone metastatic cell lines. J. Biol. Chem. 279, 3662–3670 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Eisenmann, K. M., VanBrocklin, M. W., Staffend, N. A., Kitchen, S. M. & Koo, H. M. Mitogen-activated protein kinase pathway-dependent tumor-specific survival signaling in melanoma cells through inactivation of the proapoptotic protein bad. Cancer Res. 63, 8330–8337 (2003).

    CAS  PubMed  Google Scholar 

  102. Jorgensen, K., Holm, R., Maelandsmo, G. M. & Florenes, V. A. Expression of activated extracellular signal-regulated kinases 1/2 in malignant melanomas: relationship with clinical outcome. Clin. Cancer Res. 9, 5325–5331 (2003).

    CAS  PubMed  Google Scholar 

  103. Calipel, A. et al. Mutation of B-Raf in human choroidal melanoma cells mediates cell proliferation and transformation through the MEK/ERK pathway. J. Biol. Chem. 278, 42409–42418 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Vicent, S. et al. ERK1/2 is activated in non-small-cell lung cancer and associated with advanced tumours. Br. J. Cancer 90, 1047–1052 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Mawrin, C. et al. Prognostic relevance of MAPK expression in glioblastoma multiforme. Int. J. Oncol. 23, 641–648 (2003).

    CAS  PubMed  Google Scholar 

  106. Meng, X. W. et al. Central role of Fas-associated death domain protein in apoptosis induction by the mitogen-activated protein kinase kinase inhibitor CI-1040 (PD184352) in acute lymphocytic leukemia cells in vitro. J. Biol. Chem. 278, 47326–47339 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Milella, M., Kornblau, S. M. & Andreeff, M. The mitogen-activated protein kinase signaling module as a therapeutic target in hematologic malignancies. Rev. Clin. Exp. Hematol. 7, 160–190 (2003).

    CAS  PubMed  Google Scholar 

  108. Lunghi, P. et al. Downmodulation of ERK activity inhibits the proliferation and induces the apoptosis of primary acute myelogenous leukemia blasts. Leukemia 17, 1783–1793 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Carter, C. et al. Anti-tumour efficacy of the orally active Raf kinase inhibitor BAY 43-9006 in human tumour xenograft models. Proc. Annu. Meet. Am. Assoc. Cancer Res. 42, A4954 (2001).

    Google Scholar 

  110. Wallace, E. et al. Preclinical development of ARRY-142886, a potent and selective MEK inhibitor. Proc. Annu. Meet. Am. Assoc. Cancer Res. 45, A3891 (2004).

    Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Judith S. Sebolt-Leopold.

Ethics declarations

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.

Related links

Related links

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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Issue Date:

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

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing