title: Picking the point of inhibition: a comparative review of PI3K/AKT/mTOR pathway inhibitors.
abstract: 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.
authors.affiliation: Authors' Affiliations: Molecular Therapeutics Research Unit, Medical Oncology Department; and Experimental Therapeutics Group, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Dienstmann
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodon
authors.forename: Violeta
authors.initials: V
authors.lastname: Serra
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D006801:Humans; D007527:Isoenzymes; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases