TY - JOUR
T1 - Targeting the PI3K-AKT-mTOR pathway
T2 - progress, pitfalls, and promises
AU - Yap, Timothy A.
AU - Garrett, Michelle D.
AU - Walton, Mike I.
AU - Raynaud, Florence
AU - de Bono, Johann S.
AU - Workman, Paul
N1 - Funding Information:
Work in the authors’ laboratory is funded by Cancer Research UK [CUK] programme grant number C309/A8274. Johann de Bono is funded by Cancer Research UK [CUK] programme grant number C1178/A7851. Paul Workman is a Cancer Research UK Life Fellow and Timothy Yap is a Cancer Research UK Clinical Research Fellow. The authors would like to thank Dr John Caldwell for the assistance with chemical structures.
PY - 2008/8/1
Y1 - 2008/8/1
N2 - The strategy of 'drugging the cancer kinome' has led to the successful development and regulatory approval of several novel molecular targeted agents. The spotlight is now shifting to the phosphatidylinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway as a key potential target. This review details the role of the pathway in oncogenesis and the rationale for inhibiting its vital components. The focus will be on the progress made in the development of novel therapies for cancer treatment, with emphasis placed on agents that have entered clinical development. Strategies involving horizontal and vertical blockade of the pathway, as well as the use of biomarkers to select appropriate patients and to provide proof of target modulation will also be highlighted. Finally, we discuss the issues and limitations involved with targeting the PI3K-AKT-mTOR pathway, and predict what the future may hold for these novel anticancer therapeutics.
AB - The strategy of 'drugging the cancer kinome' has led to the successful development and regulatory approval of several novel molecular targeted agents. The spotlight is now shifting to the phosphatidylinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway as a key potential target. This review details the role of the pathway in oncogenesis and the rationale for inhibiting its vital components. The focus will be on the progress made in the development of novel therapies for cancer treatment, with emphasis placed on agents that have entered clinical development. Strategies involving horizontal and vertical blockade of the pathway, as well as the use of biomarkers to select appropriate patients and to provide proof of target modulation will also be highlighted. Finally, we discuss the issues and limitations involved with targeting the PI3K-AKT-mTOR pathway, and predict what the future may hold for these novel anticancer therapeutics.
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U2 - 10.1016/j.coph.2008.08.004
DO - 10.1016/j.coph.2008.08.004
M3 - Review article
C2 - 18721898
AN - SCOPUS:51449095342
SN - 1471-4892
VL - 8
SP - 393
EP - 412
JO - Current Opinion in Pharmacology
JF - Current Opinion in Pharmacology
IS - 4
ER -