Picking the point of inhibition: a comparative review of PI3K/AKT/mTOR pathway inhibitors

• Published in: Molecular cancer therapeutics 2014-05, Vol.13 (5), p.1021-1031
• Main Authors: Dienstmann, Rodrigo, Rodon, Jordi, Serra, Violeta, Tabernero, Josep
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Humans; Isoenzymes; Neoplasms - drug therapy; Neoplasms - metabolism; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-13-0639

The frequent activation of the PI3K/AKT/mTOR pathway in cancer, and its crucial role in cell growth and survival, has made it a much desired target for pharmacologic intervention. Following the regulatory approval of the rapamycin analogs everolimus and temsirolimus, recent years have seen an explosion in the number of phosphoinositide 3-kinase (PI3K) pathway inhibitors under clinical investigation. These include: ATP-competitive, dual inhibitors of class I PI3K and mTORC1/2; "pan-PI3K" inhibitors, which inhibit all four isoforms of class I PI3K (α, β, δ, γ); isoform-specific inhibitors of the various PI3K isoforms; allosteric and catalytic inhibitors of AKT; and ATP-competitive inhibitors of mTOR only (and thus mTORC1 and mTORC2). With so many agents in development, clinicians are currently faced with a wide array of clinical trials investigating a multitude of inhibitors with different mechanisms of action, being used both as single agents and in combination with other therapies. Here, we provide a review of the literature, with the aim of differentiating the genomic contexts in which these various types of inhibitors may potentially have superior activity.