Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR.
Recent evidence places the FRAP/mTOR kinase downstream of the phosphatidyl inositol 3-kinase/Akt-signaling pathway, which is up-regulated in multiple cancers because of loss of the PTEN tumor suppressor gene. We performed biological and biochemical studies to determine whether PTEN-deficient cancer cells are sensitive to pharmacologic inhibition of FRAP/mTOR by using the rapamycin derivative CCI-779. In vitro and in vivo studies of isogenic PTEN(+/+) and PTEN(-/-) mouse cells as well as human cancer cells with defined PTEN status showed that the growth of PTEN null cells was blocked preferentially by pharmacologic FRAP/mTOR inhibition. Enhanced tumor growth caused by constitutive activation of Akt in PTEN(+/+) cells also was reversed by CCI-779 treatment, indicating that FRAP/mTOR functions downstream of Akt in tumorigenesis. Loss of PTEN correlated with increased S6 kinase activity and phosphorylation of ribosomal S6 protein, providing evidence for activation of the FRAP/mTOR pathway in these cells. Differential sensitivity to CCI-779 was not explained by differences in biochemical blockade of the FRAP/mTOR pathway, because S6 phosphorylation was inhibited in sensitive and resistant cell lines. These results provide rationale for testing FRAP/mTOR inhibitors in PTEN null human cancers.
Neshat
M S
MS
Department of Medicine, University of California School of Medicine, Los Angeles, CA 90095, USA.
Mellinghoff
I K
IK
Tran
C
C
Stiles
B
B
Thomas
G
G
Petersen
R
R
Frost
P
P
Gibbons
J J
JJ
Wu
H
H
Sawyers
C L
CL
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D039642:Eukaryotic Initiation Factors; D006801:Humans; D020104:Immunophilins / Q000037:antagonists & inhibitors*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D051059:PTEN Phosphohydrolase; D010750:Phosphoproteins / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency* / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C499527:Eif4ebp1 protein, mouse; C499526:Eif4ebp1 protein, rat; D039642:Eukaryotic Initiation Factors; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; C401859:temsirolimus; D011494:Protein Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020104:Immunophilins; D020123:Sirolimus