title: The future of targeted therapy approaches in melanoma.
abstract: BACKGROUND
  The past 30 years have seen little improvement in the survival of patients with stage IV melanoma. Following the discovery of activating BRAF mutations in most melanomas, a wealth of preclinical experimentation has validated the BRAF/MAPK pathway as an excellent therapeutic target in melanoma. Despite these encouraging results, early clinical trials on BRAF/MAPK inhibition have been disappointing.
  
  
  OBJECTIVE
  In the current review, we discuss how differences between the preclinical and clinical settings may influence the response of melanoma cells to BRAF/MEK inhibition. As the BRAF/MEK signaling pathway is not solely responsible for the growth and survival of melanoma cells, we further discuss the therapeutic utility of inhibiting the PI3K/AKT and mTOR pathways both alone and in combination with BRAF/MEK.
  
  
  CONCLUSIONS
  In looking ahead to the future, it is likely that new advances in melanoma biology, such as the identification of melanoma stem cells and a greater understanding of intratumoral heterogeneity, may play a role in the design of any future melanoma targeted therapy.
authors.affiliation: The Molecular Oncology Program and Comprehensive Melanoma Research Center, The Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
authors.forename: Liliana P
authors.initials: LP
authors.lastname: Cantini
authors.forename: Friedegund
authors.initials: F
authors.lastname: Meier
authors.forename: Vernon K
authors.initials: VK
authors.lastname: Sondak
authors.forename: Keiran Sm
authors.initials: KS
authors.lastname: Smalley