Targeting the Raf kinase cascade in cancer therapy – novel molecular targets and therapeutic strategies

Abstract

The mitogen-activated protein kinases (MAPKs) are a group of signal transducers with oncogenic potential in an assortment of cell types. Dysregulated signalling from any of the members of this family has been shown to result in development of human malignancies. Consequently, the collective goal of the scientific community is to inhibit aberrant signalling initiated from these molecules whilst minimising toxicity associated with such inhibition. This review covers events responsible for MAPK activation in detail, with an emphasis placed upon possible points of pharmacological intervention. A discussion addressing numerous chemotherapeutic approaches that have been developed over the previous decade for MAPK inhibition is also included. In addition, emphasis is placed upon the various arrays of kinase inhibitors, small molecule inhibitors, competitive inhibitors, nucleic acid aptamers and other molecules which have been proven effective in prevention of MAPK signalling. Finally, the potential therapeutic promise of many of these compounds is addressed in a manner that encompasses the complexities of MAPK signal transduction, in addition to concerns surrounding the development of drug resistance.

• Akt
• chemotherapy
• drug resistance
• epidermal growth factor (EGF)
• extracellular signal-regulated kinase (ERK)
• inhibitors
• Janus family of kinases (JAK)
• kinases
• mitogen-activated protein kinase (MAPK)
• MAPK kinase (MEK)
• oncogenes
• platelet-derived growth factor (PDGF)
• phosphatidylinositol 3´-kinase (PI3K)
• protein kinase C (PKC)
• Raf
• Ras
• signal transduction