Targeting Signaling Pathways – In the Search of Melanoma’s Achilles’ Heel

  • Nikolas K. Haass
  • Christoph Hoeller
  • Meenhard Herlyn
Part of the TTME book series (TTME, volume 2)


Melanoma is the most aggressive form of skin cancer and is highly resistant to conventional chemotherapy, immunotherapy and targeted therapy. The prognosis for metastatic melanoma remains dismal with average survival rates of 6–10 months. Dacarbazine with response rates of less than 10% and a median progression free survival of 2 months is currently the only standard agent. Despite promising results with combination chemotherapy in vitro, and better response rates in patients, no randomized clinical trial has shown a survival advantage over single agent dacarbazine. Thus, new therapeutic targets are urgently needed to improve the dismal prognosis of this disease. The mitogen activated protein kinase (MAPK) pathway is constitutively active in most melanomas. The finding that over 60% of melanomas harbor the activating BRAFV600E mutation has raised expectations for the targeted therapy of melanoma. Small molecule signalling pathway inhibitors are now available for BRAF, BRAFV600E, NRAS, MEK, mTOR, VEGF and others. In this review we discuss the role of targeting various constituents of the MAPK pathway and of mammalian target of rapamycin (mTOR). Finally we discuss the alternative approach of targeting melanoma stem cells as a putative therapy.


Targeted therapy MAPKinase BRAF Activating mutation c-KIT MEK PI3K mTOR Melanoma stem cells Multidrug resistance 


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Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Nikolas K. Haass
    • 1
    • 2
  • Christoph Hoeller
  • Meenhard Herlyn
  1. 1.The Wistar InstitutePhiladelphiaUSA
  2. 2.Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, University of SydneyNewtownAustralia

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