The RTK/RAS/BRAF/PI3K pathways in melanoma: biology, small molecule inhibitors, and potential applications

Semin Oncol. 2007 Dec;34(6):546-54. doi: 10.1053/j.seminoncol.2007.09.011.


The discovery of mutations in the BRAF signaling molecule in a large proportion of cutaneous melanomas immediately suggested the prospect of effective therapies for this disease. The most appealing initial target has been BRAF itself, as most mutations involve a single residue in the kinase domain of the protein. But the identification of the high mutation rate in this signaling intermediate also suggests that other molecules up- and downstream of BRAF might be productively targeted. Indeed, several receptor tyrosine kinases, as well as RAS, are mutated in a small number of melanoma cases. Moreover, genetic alterations in the phosphotidylinositol-3-kinase (PI3K) pathway, especially in PTEN, suggest that this route also poses opportunities for therapeutic exploitation. We will review here the genetic evidence suggesting the utility of targets on these pathways. We will also summarize the recent clinical data that have accumulated from initial trials designed to test BRAF inhibition and targeting of other molecules. Finally, we provide an overview of molecules entering the clinic and soon to be tested in clinical studies, as well as strategies for their employment as monotherapy and in combinations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Melanoma / drug therapy*
  • Melanoma / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / metabolism
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Signal Transduction
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / metabolism
  • ras Proteins / antagonists & inhibitors
  • ras Proteins / metabolism


  • Antineoplastic Agents
  • Intracellular Signaling Peptides and Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Receptor Protein-Tyrosine Kinases
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • ras Proteins