Therapeutic Kinase Inhibitors pp 99-117

Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 355)

Beyond BRAF in Melanoma



Recent progress in the analysis of genetic alterations in melanoma has identified recurrent mutations that result in the activation of critical signaling pathways promoting growth and survival of tumors cells. Alterations in the RAS-RAF-MAP kinase and PI3-kinase signaling pathways are commonly altered in melanoma. Mutations in BRAF, NRAS, KIT, and GNAQ occur in a mutually exclusive pattern and lead to MAP-kinase activation. Loss of PTEN function, primarily by deletion, is the most common known genetic alteration in the PI3-kinase cascade, and is commonly associated with BRAF mutations (Curtin et al., N Engl J Med 353:2135–2147, 2005; Tsao et al., Cancer Res 60:1800–1804, 2000, J Investig Dermatol 122:337–341, 2004). The growth advantage conveyed by the constitutive activation of these pathways leads to positive selection of cells that have acquired the mutations and in many instances leads to critical dependency of the cancer cells on their activation. This creates opportunities for therapeutic interventions targeted at signaling components within these pathways that are amenable for pharmacological inhibition. This concept follows the paradigm established by the landmark discovery that inhibition of the fusion kinase BCR-ABL can be used to treat chronic myelogenous leukemia (Druker et al., N Engl J Med 344:1031–037, 2001). The review will focus primarily on kinases involved in signaling that are currently being evaluated for therapeutic intervention in melanoma.


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© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.University of CaliforniaSan FranciscoUSA
  2. 2.Memorial Sloan-Kettering Cancer CenterNew YorkUSA

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