ESMO 2014-PATHWAY OF THE DAY

The phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway regulates essential cellular processes such as apoptosis, DNA repair, angiogenesis and metabolism

• Date: 30 Sep 2014
• Author: Sherene Loi
• Topic: Pathology/Molecular biology

This article was extracted from the Congress Daily News

The phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway (Figure) regulates essential cellular processes such as apoptosis, DNA repair, angiogenesis and metabolism. Despite its activity being tightly regulated in normal cells, deregulation of the PI3K/AKT/mTOR pathway is linked to the development of one-third of human cancers, including some breast, ovarian, prostate and non-small-cell lung cancers. In addition, deregulation of this pathway mediates resistance to conventional therapies including biological and hormonal therapies, tyrosine kinase inhibitors, radiation and cytotoxic agents.

The mechanisms driving the PI3K/AKT/mTOR pathway in cancer include amplification of PI3K genes, loss of the regulatory activity of phosphatase and tensin homologue (PTEN) and activating mutations or amplification of receptor tyrosine kinases, such as epidermal growth factor receptor family (EGFR) and HER2.

The important role of the PI3K/AKT/mTOR pathway in cancer development has made it a target for drug development efforts in recent years. Temsirolimus and everolimus are mTOR inhibitors that are in clinical use for various cancers, such as renal cell carcinoma and mantle cell lymphoma. Idelalisib, the first-in-class oral PI3K inhibitor, recently received regulatory approval for the treatment of leukaemias, including chronic lymphocytic leukaemia. Other inhibitors of AKT, PI3K and PI3K/mTOR are in clinical development. For example BYL-719, a selective PI3K inhibitor, has shown activity in patients with PI3K-mutated advanced solid tumours, including oestrogen receptor-positive metastatic breast cancer. Several dual PI3K/mTOR inhibitors (e.g. BGT-226, PF-04691502, GDC-0980 and GSK-2126458), either alone or in combination with other agents, have also demonstrated activity in early clinical studies of patients with advanced solid tumours.

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