The Mitogen-Activated Protein Kinase Pathway for Molecular-Targeted Cancer Treatment

  • Judith S. Sebolt-Leopold
  • Roman Herrera
  • Jeffrey F. Ohren
Part of the Resent Results in Cancer Research book series (RECENTCANCER, volume 172)


The molecular characterization of key events associated with tumor initiation and progression has led to the identification of cellular signaling pathways that contribute not only to normal cell functioning but also to the overall phenotype associated with cancer. One such example is the Ras-regulated kinase pathway. This signaling module, comprising Raf, mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (ERK), plays a central role in regulating a broad range of cellular events. In response to a diverse group of extracellular stimuli including growth factors, cytokines, and protooncogenes, activation of this pathway results in alterations in cell proliferation, differentiation, and survival. It is therefore not surprising that this pathway has been found to be upregulated in a large percentage of human tumors. While contributing to the uncontrolled growth and enhanced survival of tumor cells, the Ras-MAP kinase pathway also plays a key role in their metastatic spread by regulating cell motility and invasion.


Papillary Thyroid Carcinoma BRAF Mutation Conserve Phosphorylation Site Kinase Domain Structure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ahn NG, Nahreini TS, Tolwinski NS, Resing KA (2001) Pharmacological inhibitors of MKK1 and MKK2. Methods Enzymol 332:417–431PubMedCrossRefGoogle Scholar
  2. Allen LF, Sebolt-Leopold J, Meyer MB (2003) CI-1040 (PD184352), a targeted signal transduction inhibitor of MEK (MAPKK). Semin Oncol 30:105–116PubMedCrossRefGoogle Scholar
  3. Alessi DR, Saito Y, Campbell DG, Cohen P, Sithanaandam G, Rapp U, Ashwort A, Marshall C, Cowley S (1994) Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1. EMBO J 13:1610–1619PubMedGoogle Scholar
  4. Baccarini M (2005) Second nature: biological functions of the Raf-1 “kinase”. FEBS Lett 579:3271–327PubMedCrossRefGoogle Scholar
  5. Beeram M, Patnaik A, Rowinsky EK (2005) Raf:a strategic target for therapeutic development against cancer. J Clin Oncol 23:6771–6790PubMedCrossRefGoogle Scholar
  6. Bild AH, Yao G, Chang JT, Wang Q, Potti A, Chasse D, Joshi MB, Harpole D, Lancaster JM, Berchuck A, Olson JA Jr, Marks JR, Dressman HK, West M, Nevins JR (2006) Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 439:353–357PubMedCrossRefGoogle Scholar
  7. Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME (1999) Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and-independent mechanisms. Science 286:1358–1362PubMedCrossRefGoogle Scholar
  8. Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, Einhorn E, Herlyn M, Minna J, Nicholson A, Roth JA, Albelda SM, Davies H, Cox C, Brignell G, Stephens P, Futreal PA, Wooster R, Stratton MR, Weber BL (2002) BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 62:6997–7000PubMedGoogle Scholar
  9. Brott BK, Alessandrini A, Largaespada DA, Copeland NG, Jenkins NA, Crews CM, Erikson RL (1993) MEK2 is a kinase related MEK1 and is differentially expressed in murine tissues. Cell Growth Differ 4:921–929PubMedGoogle Scholar
  10. Busca R, Abbe P, Mantoux F, Aberdam E, Peyssonnaux C, Eychene A, Ortonne JP, Ballotti R (2000) Ras mediates the cAMP-dependent activation of extracellular signal-regulated kinases (ERKs) in melanocytes. EMBO J 19:2900–2910PubMedCrossRefGoogle Scholar
  11. Catling AD, Schaeffer HJ, Reuter CW, Reddy GR, Weber MJ. (1995) A proline-rich sequence unique to MEK1 and MEK2 is required for Raf binding and regulates MEK function. Mol Cell Biol 15:5214–5225PubMedGoogle Scholar
  12. Chen Z, Gibson TB, Robinson F, Silvestro L, Pearson G, Xu B, Wright A, Vanderbilt C, Cobb MH (2001) MAP kinases. Chem Rev 101:2449–2476PubMedCrossRefGoogle Scholar
  13. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954PubMedCrossRefGoogle Scholar
  14. Davies SP, Reddy H, Caivano M, Cohen P (2000) Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 351:95–105PubMedCrossRefGoogle Scholar
  15. Derynck R, Akhurst RJ, Balmain A (2001) TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 29:117–129PubMedCrossRefGoogle Scholar
  16. Downward J (2003) Targeting ras signalling pathways in cancer therapy. Nat Rev Cancer 3:11–22PubMedCrossRefGoogle Scholar
  17. Downward J (2006) Signatures guide drug choice. Nature 439:274–275PubMedCrossRefGoogle Scholar
  18. Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR (1995) A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA 92:7686–7689PubMedCrossRefGoogle Scholar
  19. Farooq A, Zhou MM (2004) Structure and regulation of MAPK phosphatases. Cell Signal 16:769–779.PubMedCrossRefGoogle Scholar
  20. Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, Van Dyk DE, Pitts WJ, Earl RA, Hobbs F, Copeland RA, Magolda RL, Scherle PA, Trzaskos JM (1998) Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 273:18623–18632PubMedCrossRefGoogle Scholar
  21. Frost JA, Steen H, Shapiro P, Lewis T, Ahn N, Shaw PE, Cobb MH (1997) Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins. EMBO J 16:6426–6438PubMedCrossRefGoogle Scholar
  22. Fukuda M, Gotoh Y, Nishida E (1997) Interaction of MAP kinase with MAP kinase kinase:its possible role in the control of nucleocytoplasmic transport of MAP kinase. EMBO J 16:1901–1908PubMedCrossRefGoogle Scholar
  23. Gopalbhai K, Jansen G, Beauregard G, Whiteway M, Dumas F, Wu C, Meloche S (2003) Negative regulation of MAPKK by phosphorylation of a conserved serine residue equivalent to Ser212 of MEK1. J Biol Chem 278:8118–8125PubMedCrossRefGoogle Scholar
  24. Hagemann C and Rapp UR (1999) Isotype-specific functions of Raf kinases. Exp Cell Res 253:34–46PubMedCrossRefGoogle Scholar
  25. Hanks SK and Quinn AM (1991) Protein kinase catalytic domain sequence database: identification of conserved features of primary structure and classification of family members. Methods Enzymol 200:38–62PubMedGoogle Scholar
  26. Haystead TA, Dent P, Wu J, Haystead CM, Sturgill TW (1992) Ordered phosphorylation of p42mapk by MAP kinase kinase. FEBS Lett 306:17–22PubMedCrossRefGoogle Scholar
  27. Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-I S, Wada H, Fujimoto J, Kohno M (1999) Constitutive activation of the 41-/43-Da mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 18:813–822PubMedCrossRefGoogle Scholar
  28. Iacovelli L, Capobianco L, Salvatore L, Sallese M, D’Ancona GM, DeBlasi A (2001) Thyrotropin activates mitogen-activated protein kinase pathway in FRTL-5 by a cAMP-dependent protein kinase A-independent mechanism. Mol Pharmacol 60:924–933PubMedGoogle Scholar
  29. Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA (2003) 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 63:1454–1457PubMedGoogle Scholar
  30. Kolch W (2005) Coordinating ERK/MAPK signaling through scaffolds and inhibitors. Nat Rev Mol Cell Biol 6:827–837PubMedCrossRefGoogle Scholar
  31. Lackey K, Cory M, Davis R, Frye SV, Harris PA, Hunter RN, Jung DK, McDonald OB, McNutt RW, Peel MR, Rutkowske RD, Veal JM, Wood ER (2000) The discovery of potent cRaf1 kinase inhibitors. Bioorg Med Chem Lett 10:223–226PubMedCrossRefGoogle Scholar
  32. Lavoie JN, L’Allemain G, Brunet A, Muller R, Pouyssegur J (1996) Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J Biol Chem 271:20608–20616PubMedCrossRefGoogle Scholar
  33. LoRusso PM, Adjei, AA, Varterasian M, Gadgeel S, Reid J, Mitchell DY, Hanson L, deLuca P, Bruzek L, Piens J, Asbury P, VanBecelaere K, Herrera R, Sebolt-Leopold JS, Meyer MB (2005) Phase 1 and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 23:5281–5293PubMedCrossRefGoogle Scholar
  34. LoRusso PM, Krishnamurthi S, Rinehart JR, Nabell L, Croghan G, Varterasian M, Sadis S, Menon SS, Leopold J, Spear MA, Meyer MB (2005) A phase 1-2 clinical study of a second generation oral MEK inhibitor, PD0325901 in patients with advanced cancer. Proc Am Soc Clin Oncol 24:Abst 3011Google Scholar
  35. Maloney A and Workman P (2002) HSP90 as a new therapeutic target for cancer therapy:the story unfolds. Expert Opin Biol Ther 2:3–24PubMedCrossRefGoogle Scholar
  36. Marais R, Light Y, Paterson HF, Mason CS, Marshall CJ (1997) Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic ras and tyrosine kinases. J Biol Chem 272:4378–4383PubMedCrossRefGoogle Scholar
  37. Mercer KE and Pritchard CA (2003) Raf proteins and cancer:B-Raf is identified as a mutational target. Biochim Biophys Acta 1653:25–40PubMedGoogle Scholar
  38. Ohren JF, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P, Yan C, McConnell P, Spessard C, Banotai C, Mueller WT, Delaney A, Omer C, Sebolt-Leopold J, Dudley DT, Leung IK, Flamme C, Warmus J, Kaufman M, Barrett S, Tecle H, Hasemann CA (2004) Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol 11:1192–1197PubMedCrossRefGoogle Scholar
  39. Papin C, Denouel A, Calothy G, Eychene A (1996) Identification of signalling proteins interacting with B-Raf in the yeast two-hybrid system. Oncogene 12:2213–2221PubMedGoogle Scholar
  40. Pollock PM and Meltzer PS (2002) A genome-based strategy uncovers frequent BRAF mutations in melanoma. Cancer Cell 2:5–7PubMedCrossRefGoogle Scholar
  41. Pruitt K, Der CJ (2001) Ras and Rho regulation of the cell cycle and oncogenesis. Cancer Lett. 171:1–10PubMedCrossRefGoogle Scholar
  42. Rinehart J, Adjei AA, LoRusso PM, Waterhouse D, Hecht JR, Natale RB, Hamid O, Varterasian M, Asbury P, Kaldjian EP, Gulyas S, Mitchell DY, Herrera R, Sebolt-Leopold JS, Meyer MB (2004) Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol 22:4456–4462PubMedCrossRefGoogle Scholar
  43. Satyamoorthy K, Li G, Gerrero MR, Brose MS, Volpe P, Weber BL, VanBelle P, Elder DE, Herlyn M (2003) Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res 63:756–759PubMedGoogle Scholar
  44. Schaeffer HJ, Catling AD, Eglen ST, Collier LS, Krauss A, Weber MJ (1998) MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. Science 281:1668–1671PubMedCrossRefGoogle Scholar
  45. Sebolt-Leopold JS (2004) MEK inhibitors:a therapeutic approach to targeting the Ras-MAP kinase pathway in tumors. Curr Pharm Design 10:1907–1914CrossRefGoogle Scholar
  46. Sebolt-Leopold JS and Herrera R (2004) Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 4:937–947PubMedCrossRefGoogle Scholar
  47. Sebolt-Leopold JS and English JM (2006) Mechanisms of drug inhibition of signaling molecules. Nature, 441:457–462.PubMedCrossRefGoogle Scholar
  48. Sebolt-Leopold JS, Dudley DT, Herrera R, Van Becelaere K, Wiland A, Gowan RC, Tecle H, Barrett SD, Bridges A, Przybranowski S, Leopold WR, Saltiel AR (1999) Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nature 5:810–816.CrossRefGoogle Scholar
  49. Seger R, Ahn NG, Posada J, Munar ES, Jensen AM, Cooper JA, Cobb MH, Krebs EG (1992) Purification and characterization of mitogen-activated protein kinase activator(s) from epidermal growth factor-stimulated A431 cells. J Biol Chem 267:14373–14381PubMedGoogle Scholar
  50. Shelton JG, Moye PW, Steelman LS, Blalock WL, Lee JT, Franklin RA, McMahon M, McCubrey JA (2003) Differential effects of kinase cascade inhibitors on neoplastic and cytokine-mediated cell proliferation. Leukemia 17:1765–1782PubMedCrossRefGoogle Scholar
  51. Shimamura A, Ballif BA, Richards SA, Blenis J (2000) Rsk1 mediates a MEK-MAP kinase cell survival signal. Curr. Biol. 10:127–135PubMedCrossRefGoogle Scholar
  52. Singer G, Oldt RIII, Cohen Y, Wang BG, Sidransky D, Kurman RJ, Shih IeM (2003) Mutations in BRAF and KRAS characterize the development of lowgrade ovarian serous carcinoma. J Natl Cancer Inst 95:484–486PubMedCrossRefGoogle Scholar
  53. Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, Ye Q, Lobo JM, She Y, Osman I, Golub TR, Sebolt-Leopold J, Sellers WR, Rosen N (2006) BRAF mutation predicts sensitivity to MEK inhibition. Nature 439:358–362PubMedCrossRefGoogle Scholar
  54. Sridhar SS, Hedley D, Siu LL (2005) Raf kinase as a target for anticancer therapeutics. Mol Cancer Ther 4:677–685PubMedCrossRefGoogle Scholar
  55. Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA (2004) JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia 18:189–218PubMedCrossRefGoogle Scholar
  56. Takekawa M, Tatebayashi K, Saito H (2005) Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases. Mol Cell 18:295–306PubMedCrossRefGoogle Scholar
  57. Thompson N and Lyons J (2005) Recent progress in targeting the Raf/MEK/ERK pathway with inhibitors in cancer drug discovery. Curr Opin Pharm 5:350–356CrossRefGoogle Scholar
  58. Wallace EM, Lyssikatos JP, Yeh T, Winkler JD, Koch K (2005) Progress towards therapeutic small molecule MEK inhibitors for use in cancer therapy. Curr Top Med Chem 5:215–229PubMedCrossRefGoogle Scholar
  59. Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R, Cancer Genome Project (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116:855–867PubMedCrossRefGoogle Scholar
  60. Wellbrock C, Karasarides M, Marais R (2004) The Raf proteins take centre stage. Nat Rev Mol Cell Biol 5:875–885PubMedCrossRefGoogle Scholar
  61. Wilhelm SM, Carter C, Tang LY, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099–7109PubMedCrossRefGoogle Scholar
  62. Zheng CF and Guan KL (1993) Properties of MEKs, the kinases that phosphorylate and activate the extracellular signal-regulated kinases. J Biol Chem 268:23933–23939PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2007

Authors and Affiliations

  • Judith S. Sebolt-Leopold
    • 1
  • Roman Herrera
    • 1
  • Jeffrey F. Ohren
    • 1
  1. 1.Pfizer Global Research and DevelopmentMichigan LaboratoriesAnn ArborUSA

Personalised recommendations