TY - JOUR
T1 - Pushing the envelope in the mTOR pathway
T2 - The second generation of inhibitors
AU - Vilar, Eduardo
AU - Perez-Garcia, Jose
AU - Tabernero, Josep
PY - 2011/3
Y1 - 2011/3
N2 - The phosphatidylinositol-3-kinase (PI3K)/mTOR pathway has been a major focus of attention for cancer researchers in the past decade. A preliminary and incomplete understanding of the molecular biology of this complex network has importantly conditioned not only the development of the first generation of mTOR inhibitors, but also the biomarker studies designed to identify the best responders to these agents. Most recently, research in this pathway has focused on the dual nature of mTOR that is integrated by the mTOR complex 1 and complex 2. These two complexes are formed and regulated by different proteins and are also driven by multiple different compensatory feedback loops. This deeper understanding has allowed the development of a promising second generation of inhibitors, which are able to block simultaneously both complexes due to their catalytic activity over mTOR. Moreover, some of them also exert an inhibitory effect over PI3K that is a key player in the feedback loops. This article reviews the newest insights in the signaling of the mTOR pathway and then focuses on the development of the new wave of mTOR inhibitors.
AB - The phosphatidylinositol-3-kinase (PI3K)/mTOR pathway has been a major focus of attention for cancer researchers in the past decade. A preliminary and incomplete understanding of the molecular biology of this complex network has importantly conditioned not only the development of the first generation of mTOR inhibitors, but also the biomarker studies designed to identify the best responders to these agents. Most recently, research in this pathway has focused on the dual nature of mTOR that is integrated by the mTOR complex 1 and complex 2. These two complexes are formed and regulated by different proteins and are also driven by multiple different compensatory feedback loops. This deeper understanding has allowed the development of a promising second generation of inhibitors, which are able to block simultaneously both complexes due to their catalytic activity over mTOR. Moreover, some of them also exert an inhibitory effect over PI3K that is a key player in the feedback loops. This article reviews the newest insights in the signaling of the mTOR pathway and then focuses on the development of the new wave of mTOR inhibitors.
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U2 - 10.1158/1535-7163.MCT-10-0905
DO - 10.1158/1535-7163.MCT-10-0905
M3 - Review article
C2 - 21216931
AN - SCOPUS:79955785100
SN - 1535-7163
VL - 10
SP - 395
EP - 403
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 3
ER -