University of Dundee

Insight into an anti-cancer drug target and tools for life sciences research

A key regulator of cell growth and survival called PKB (also called AKT) is the focus of numerous anti-cancer drug clinical trials. The role of this protein and how it is switched on was uncovered by researchers in Dundee and has stimulated pharmaceutical companies to undertake drug development campaigns focused on PKB as a target molecule. Moreover, this research led several life sciences companies to generate research tools to accelerate academic and industry research in this area.

The protein PKB regulates many cellular functions including metabolism, growth, and proliferation. PKB was identified in the early 1990s and interest was sparked by the finding that increased PKB expression and activity was detected in aggressive cancers, such as gastric, breast, prostate, ovarian and brain tumors. In 1995, the laboratory of Professor Sir Philip Cohen FRS FRSE at the University of Dundee identified a protein called GSK3 as the first physiological substrate of PKB. Shortly after, Professor Dario Alessi FRS FRSE in a series of seminal papers uncovered the mechanism by which PKB was activated, demonstrating that it involved the attachment of phosphate to particular sites on the protein. Moreover, he identified the protein called PDK1 that switched on PKB activity.  Subsequent structural studies at the University involving Professor Daan van Aalten FRSE provided important insights for the design of small molecules permitting targeted inhibition of PDK1.

Clinical studies measuring PKB activity in tumours have used the phosphorylation sites identified by Professor Alessi as a marker of its hyperactivation. For example in breast cancer patients, hyper-activation of PKB is associated with poor prognosis and increased probability of relapse accompanied by distant metastases. PKB is a firmly established focus for pharmacological intervention and there has been a huge effort by numerous academic groups worldwide to understand better the complex signaling pathways that involve PKB, particularly in cancer. The work in Dundee has contributed to this effort. Several clinical trials are underway testing the antineoplastic activity of PKB inhibitors in a variety of cancers.

This research has also stimulated biotechnology companies to develop reagents to help researchers probe this signaling pathway in normal and diseased tissue. Antibodies specific to the key sites on PKB are used to measure its activation, and kits to measure the effects of PKB on downstream targets are sold by many life science companies as a direct result of discoveries made by researchers in the School of Life Sciences.