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:

Review Article

Development of anticancer drugs targeting the MAP kinase pathway

Oncogene volume 19, pages 6594–6599 (2000)Cite this article

Abstract

Since the discovery of the role of ras oncogenes in tumorigenesis, we have witnessed an explosion of research in the signal transduction area. In the quest to understand how Ras transmits extracellular growth signals, the MAP kinase (MAPK) pathway has emerged as the crucial route between membrane-bound Ras and the nucleus. The MAPK pathway encompasses a cascade of phosphorylation events involving three key kinases, namely Raf, MEK (MAP kinase kinase) and ERK (MAP kinase). This kinase cascade presents novel opportunities for the development of new cancer therapies designed to be less toxic than conventional chemotherapeutic drugs. Furthermore, as a signal transduction-based approach to cancer treatment, inhibition of any one of these targets has the potential for translational pharmacodynamic evaluation of target suppression. The rationale for targeting the MAP kinase pathway will be reviewed here along with a discussion of various pharmacological approaches and the promise they hold for a new generation of anticancer drugs.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Alessi DR, Cuenda A, Cohen P, Dudley DT and Saltiel AR. . 1995 J. Biol. Chem. 270: 27489–27494.

  • Allen M, Svensson L, Roach M, Hambor J, McNeish J and Gabel CA. . 2000 J. Exp. Med. 191: 859–869.

  • Anderson NG, Maller JL, Tonks NK and Sturgill TW. . 1990 Nature 343: 651–653.

  • Bayer Corporation. . 1999a WO9932106.

  • Bayer Corporation. . 1999b WO9932436.

  • Bayer Corporation. . 1999c WO9932455.

  • Bayer Corporation. . 2000 WO200042012.

  • Boucher MJ, Morisset J, Vachon PH, Reed JC, Laine J and Rivard N. . 2000 J. Cell. Biochem. 79: 355–369.

  • Brunet A, Pages G and Pouyssegur J. . 1994 FEBS Lett. 346: 299–303.

  • Chen Q, Kinch MS, Lin TH, Burridge K and Juliano RL. . 1994 J. Biol. Chem. 269: 26602–26605.

  • Cobb MH. . 1999 Prog. Biophys. Mol. Biol. 71: 479–500.

  • Cowley S, Paterson H, Kemp P and Marshall CJ. . 1994 Cell 77: 841–852.

  • Crews CM, Alessandrini A and Erikson RL. . 1992 Science 258: 478–480.

  • Daum G, Eisenmann-Tappe I, Fries HW, Troppmair J and Rapp UR. . 1994 Trends Biochem. Sci. 19: 474–480.

  • Dent P, Haser W, Haystead TA, Vincent LA, Roberts TM and Sturgill TW. . 1992 Science 257: 1404–1407.

  • Dudley DT, Pang L, Decker SJ, Bridges AJ and Saltiel AR. . 1995 Proc. Natl. Acad. Sci. USA 92: 7686–7689.

  • Eliceiri BP, Klemke R, Stromblad S and Cheresh DA. . 1998 J. Cell Biol. 141: 1255–1263.

  • Fang X, Yu S, Eder A, Mao M, Bast Jr RC, Boyd D and Mills GB. . 1999 Oncogene 18: 6635–6640.

  • Fincham VJ, James M, Frame MC and Winder SJ. . 2000 EMBO J. 19: 2911–2923.

  • Finlay D, Healy V, Furlong F, O'Connell FC, Keon NK and Martin F. . 2000 Cell Death Differ. 7: 303–313.

  • Gille H, Sharrocks AD and Shaw PE. . 1992 Nature 258: 414–417.

  • Gioeli D, Mandell JW, Petroni GR, Frierson Jr HF and Weber MJ. . 1999 Cancer Res. 59: 279–284.

  • Giroux S, Tremblay M, Bernard D, Cardin-Girard JF, Aubry S, Larouche L, Rousseau S, Huot J, Landry J, Jeannotte L and Charon J. . 1999 Curr. Biol. 9: 369–372.

  • Hagemann C and Rapp UR. . 1999 Exp. Cell Res. 253: 34–46.

  • Hall-Jackson CA, Eyers PA, Cohen P, Goedert M, Boyle FT, Hewitt NH and Hedge P. . 1999 Chem. Biol. 6: 559–568.

  • Henry SP, Monteith D, Bennett F and Levin AA. . 1997 Anticancer Drug Des. 12: 409–420.

  • Her JH, Lakhani S, Zu K, Vila J, Dent P, Sturgill TW and Weber MJ. . 1993 Biochem. J. 296: 25–31.

  • Herrera R. . 1998 J. Cell Science 111: 1039–1049.

  • Hill CS and Treisman R. . 1995 Cell 80: 199–211.

  • Holmstrom TH, Tran SE, Johnson VL, Ahn NG, Chow SC and Eriksson JE. . 1999 Mol. Cell. Biol. 19: 5991–6002.

  • Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-I S, Wada H, Fujimoto J and Kohno M. . 1999 Oncogene 18: 813–822.

  • Janknect R, Ernst WH, Pingoud V and Nordheim A. . 1993 EMBO J. 12: 5097–5104.

  • Kolch W. . 2000 Biochem. J. 351: 289–305.

  • Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, Mischak H, Finkenzeller G, Marme D and Rapp UR. . 1993 Nature 364: 249–252.

  • Lange CA, Richer JK, Shan T and Horwitz KB. . 1996 J. Biol. Chem. 273: 31308–31316.

  • Lee SW, Fang L, Igarashi M, Ouchi T, Lu KP and Aaronson SA. . 2000 Proc. Natl. Acad. Sci. USA 97: 8302–8305.

  • Lenormand P, Brondello JM, Brunet A and Pouyssegur J. . 1998 J. Cell. Biol. 142: 625–633.

  • Lewis TS, Shapiro PS and Ahn NG. . 1998 Adv. Cancer Res. 74: 49–139.

  • Li W, Han M and Guan K-L. . 2000 Genes Dev. 14: 895–900.

  • Lu H-T, Yang DD, Wysk M, Gatti E, Mellman I, Davis RJ and Flavell RA. . 1999 EMBO J. 18: 1845–1857.

  • Mansour SJ, Matten WT, Hermann AS, Candia JM, Rong S, Fukasawa K, Vande Woude GF and Ahn NG. . 1994 Science 265: 966–970.

  • Marais R, Wynne J and Treisman R. . 1993 Cell 73: 381–393.

  • McDonald OB, Chen WJ, Ellis B, Hoffman C, Overton L, Rink M, Smith A, Marshall CJ and Wood ER. . 1999 Anal. Biochem. 268: 318–329.

  • Milanini J, Vinals F, Pouyssegur J and Pages G. . 1998 J. Biol. Chem. 273: 18165–18172.

  • Monia BP, Johnston JF, Geiger T, Muller M and Fabbro D. . 1996 Nature Med. 2: 668–675.

  • O'Dwyer PJ, Stevenson JP, Gallagher M, Cassella A, Vasilevskaya I, Monia BP, Holmlund J, Dorr FA and Yao KS. . 1999 Clin. Cancer Res. 5: 3977–3982.

  • Pages G, Lenorman D, L'Allemain G, Chambard JC, Meloche S and Pouyssegur J. . 1993 Proc. Natl. Acad. Sci. USA. 90: 8319–8323.

  • Pages G, Guerin S, Grall D, Bonino F, Smith A, Anjuere F, Auberger P and Pouyssegur J. . 1999 Science 286: 1374–1377.

  • Pang L, Sawada T, Decker SJ and Saltiel AR. . 1995 J. Biol. Chem. 270: 13585–13588.

  • Persons DL, Yazlovitskaya EM, Cui W and Pelling JC. . 1999 Clin. Cancer Res. 5: 1007–1014.

  • Persons DL, Yazlovitskaya EM and Pelling JC. . 2000 J. Biol. Chem. in press.

  • Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B and Kerbel RS. . 1997 Am. J. Pathol. 151: 1523–1530.

  • Potempa S and Ridley AJ. . 1998 Mol. Biol. Cell. 9: 2185–2200.

  • Ridley AJ, Comoglio PM and Hall A. . 1995 Mol. Cell Biol. 15: 1110–1122.

  • Schaeffer HJ, Catling AD, Eblen ST, Collier LS, Krauss A and Weber MJ. . 1998 Science 281: 1668–1671.

  • Scheid MP, Schubert KM and Duronio V. . 1999 J. Biol. Chem. 274: 31108–31113.

  • Sebolt-Leopold JS, Dudley DT, Herrera R, Van Becelaere K, Wiland A, Gowan RC, Tecle H, Barrett SD, Bridges A, Przybranowski S, Leopold WR and Saltiel AR. . 1999 Nature Med. 5: 810–816.

  • Seger R, Ahn NG, Posada J, Munar ES, Jensen AM, Cooper JA, Cobb MH and Krebs EG. . 1992 J. Biol. Chem. 267: 14373–14381.

  • Stanton Jr VP and Cooper GM. . 1987 Mol. Cell. Biol. 7: 1171–1179.

  • Stevenson JP, Yao K-S, Gallagher M, Friedland D, Mitchell EP, Cassella A, Monia B, Kwoh TJ, Yu R, Holmlund J, Dorr FA and O'Dwyer PJ. . 1999 J. Clin. Oncol. 17: 2227–2236.

  • Stewart S, Sundaram M, Zhang Y, Lee J, Han M and Guan K-L. . 1999 Mol. Cell. Biol. 19: 5523–5534.

  • Stokoe D, Macdonald SG, Cadwallader K, Symons M and Hancock JF. . 1994 Science 264: 1463–1467.

  • Storm SM and Rapp UR. . 1993 Toxicol. Lett. 67: 201–210.

  • Tanimura S, Chatani Y, Hoshino R, Sato M, Watanabe S, Kataoka T, Nakamura T and Kohno M. . 1998 Oncogene 17: 57–68.

  • Wang H-G, Rapp UR and Reed JC. . 1996 Cell 87: 629–638.

  • Wang X, Martindale JL and Holbrook NJ. . 2000 J. Biol. Chem. In press.

  • Weber CK, Slupsky JR, Herrmann C, Schuler M, Rapp UR and Block C. . 2000 Oncogene 19: 169–176.

  • Welch DR, Sakamaki T, Pioquinto R, Leonard TO, Goldberg SF, Hon Q, Erikson RL, Rieber M, Rieber MS, Hicks DJ, Bonventre JV and Alessandrini A. . 2000 Cancer Res. 60: 1552–1556.

  • Yuen AR and Sikic BI. . 2000 Frontiers Biosci. D588–593.

  • Yeung K, Seitz T, Li S, Janosch P, McFerran B, Kaiser C, Fee F, Katsanakis KD, Rose DW, Mischak H, Sedivy JM and Kolch W. . 1999 Nature 401: 173–177.

  • Yeung K, Janosch P, McFerran B, Rose DW, Mischak H, Sedivy JM and Kolch W. . 2000 Mol. Cell. Biol. 20: 3079–3085.

  • Yung Y, Yao Z, Hanoch T and Seger R. . 2000 J. Biol. Chem. 275: 15799–15808.

  • Zecevic M, Catling AD, Eblen ST, Renzi L, Hittle JC, Yen TJ, Gorbsky GJ and Weber MJ. . 1998 J. Cell Biol. 142: 1547–1558.

  • Zeneca Ltd. . 1998 WO9822103.

  • Zhu X and Assoian RK. . 1995 Mol. Biol. Cell 6: 273–282.

Download references

Acknowledgements

The author would like to thank Drs Roman Herrera, Jennifer Swanteck and WR Leopold for helpful comments in their critical review of this manuscript.

Author information

Authors and Affiliations

  1. Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48105, Michigan, USA

    Judith S Sebolt-Leopold

Authors
  1. Judith S Sebolt-Leopold
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sebolt-Leopold, J. Development of anticancer drugs targeting the MAP kinase pathway. Oncogene 19, 6594–6599 (2000). https://doi.org/10.1038/sj.onc.1204083

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204083

Keywords

This article is cited by

Search

Advanced search

Quick links