Targeting Akt in cancer therapy

In an effort to improve therapeutic options in cancer, many investigational drugs are being developed to inhibit signaling pathways that promote the survival of cancer cells. The prototypic pathway that promotes cellular survival is the phosphoinositide 3′-kinase/Akt/mammalian target of rapamycin pathway, which is constitutively activated in many types of cancers. Mechanisms for activation of the serine/threonine kinase, Akt, include loss of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) function, amplification or mutation of phosphoinositide 3′-kinase, amplification of Akt, activation of growth factor receptors and exposure to carcinogens. Activation of Akt promotes cellular survival as well as resistance to treatment with chemotherapy and/or radiation therapy. Immunohistochemical analyses have shown that Akt is activated in many types of cancers and preneoplastic lesions, and Akt activation is a poor prognostic factor in various cancers. Taken together, these data demonstrate that Akt is a valid target for inhibition. This review will focus on published data using different approaches to inhibit Akt. We will also consider how the complex regulation of the phosphoinositide 3′-kinase/Akt/mammalian target of rapamycin pathway poses practical issues concerning the design of clinical trials, potential toxicities and the likelihood of finding a therapeutic index when targeting such a critical cellular pathway.