The ABCs of Targeting Raf: Novel Approaches to Cancer Therapy
The Ras/Raf signaling pathway mediates key signaling events involved in cell proliferation and angiogenesis and provides several targets for the development of therapeutic inhibitors. Raf kinases are a family of serine/threonine protein kinases that mediate many signaling events in response to growth factor signaling. Inappropriate activation of the MAP kinase pathway happens either through constitutive activation of growth factor receptors or through activating mutations in Ras and Raf. Such inappropriate activation can lead to growth factor independent proliferation, inactivation of tumor suppressor genes, angiogenesis, invasion, and metastasis. These activating mutations can also lead to suppression of apoptosis and resistance to chemotherapy. In essence, mutations of this pathway can lead to all of the hallmarks of cancer. Overactivation of the Ras/Raf/MEK/ERK pathway is common in most human malignancies. Therefore, all components of this cascade are attractive targets for anticancer therapies. In this context, certain Raf kinase inhibitors have been found to have significant anti-cancer activities and have been approved for clinical use recently. This review outlines the Raf family members structurally and functionally, and the strategies that are being developed to target them as anti-cancer agents.
Keywords: Raf-1, B-Raf, sorafenib, targeted therapy
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