TY - JOUR
T1 - Picking the point of inhibition
T2 - A comparative review of PI3K/AKT/mTOR pathway inhibitors
AU - Dienstmann, Rodrigo
AU - Rodon, Jordi
AU - Serra, Violeta
AU - Tabernero, Josep
PY - 2014/5
Y1 - 2014/5
N2 - 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: ATPcompetitive, dual inhibitors of class I PI3K and mTORC1/2; "pan-PI3K" inhibitors, which inhibit all four isoforms of class I PI3K (a, b, d, g); 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.
AB - 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: ATPcompetitive, dual inhibitors of class I PI3K and mTORC1/2; "pan-PI3K" inhibitors, which inhibit all four isoforms of class I PI3K (a, b, d, g); 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.
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U2 - 10.1158/1535-7163.MCT-13-0639
DO - 10.1158/1535-7163.MCT-13-0639
M3 - Review article
C2 - 24748656
AN - SCOPUS:84899850988
SN - 1535-7163
VL - 13
SP - 1021
EP - 1031
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 5
ER -