Targeting PI3K signalling in cancer: opportunities, challenges and limitations

Key Points There are several therapeutics that target the PI3K–Akt pathway in clinical development for the treatment of cancer. These include dual PI3K–mTOR inhibitors, PI3K inhibitors, Akt inhibitors and mTOR complex catalytic site inhibitors. The PI3K–Akt pathway is inappropriately activated in many cancers. The pathway is activated by receptor tyrosine kinases, as well as by the genetic mutation and amplification of key pathway components. The most effective type of therapeutic used to inhibit this pathway is likely to depend on the particular mechanism of PI3K–Akt activation in a cancer. So far, preclinical data suggest that PI3K–Akt pathway inhibitors might have single-agent activity in breast cancers with ERBB2 amplifications or PIK3CA mutations. These drugs might also be effective in overcoming acquired resistance to therapies that target receptor tyrosine kinases (such as acquired resistance to trastuzumab or erlotinib). Drugs targeting the PI3K–Akt pathway might most effectively treat cancers when they are used in combination with other targeted therapies, such as MEK inhibitors. Effective clinical development will centre on determining why these compounds fail when they do. It will be important to determine whether a drug could not effectively downregulate PI3K–Akt signalling or if effective inhibition of the pathway was not sufficient to produce a clinical response. The PI3K–Akt pathway is vital to the growth and survival of cancer cells and consequently inhibitors targeting this pathway are entering clinical trials. What is the therapeutic potential of such drugs and what might the challenges and limitations be? There are ample genetic and laboratory studies that suggest the PI3K–Akt pathway is vital to the growth and survival of cancer cells. Inhibitors targeting this pathway are entering the clinic at a rapid pace. In this Review, the therapeutic potential of drugs targeting PI3K–Akt signalling for the treatment of cancer is discussed. I focus on the advantages and drawbacks of different treatment strategies for targeting this pathway, the cancers that might respond best to these therapies and the challenges and limitations that confront their clinical development.