The Mitogen-Activated Protein Kinase Pathway for Molecular-Targeted Cancer Treatment
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.
KeywordsPapillary Thyroid Carcinoma BRAF Mutation Conserve Phosphorylation Site Kinase Domain Structure
Unable to display preview. Download preview PDF.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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