Targeted Inhibition of AKT in Pancreatic Cancer

Tawnya   L.   Bowles; Colin      Parsons; Diego   J.   Muilenburg; Richard   J.   Bold

doi:10.2174/157339409789712654

Abstract

The understanding of the barriers to effective treatment of cancer is rapidly expanding. As the molecular pathways of apoptosis become better understood, the mechanisms by which cancer cells evade the apoptotic effect of standard chemotherapeutic agents are revealed. Protein kinase B/AKT mediates a potent survival/anti-apoptotic signal when activated; many cancers have been observed to harbor constitutive activation. The mechanism of constitutive activation of AKT in cancer is not usually due to mutation or amplification of the gene, but through activation of upstream signaling events. Extensive preliminary data has shown that inhibition of AKT restores apoptotic sensitivity in various cancers to diverse chemotherapeutic agents, yet the optimal mechanism of inhibition of AKT has yet to be clearly defined. Pancreatic cancer is one of the most difficult to treat given its extreme resistance to the cytotoxic effect of traditional therapy; investigations into therapies to restore apoptotic sensitivity have identified AKT as a potenial target for inhibition. The evolving targeted inhibition of AKT, whether directly or indirectly, is an active area of research with tremendous potential in cancer therapy, and pancreatic cancer specifically, and this field of research is discussed in the current review.

Keywords: Akt, pancreatic cancer, NF-κB, autophagy, apoptosis

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