mTOR signaling in glioblastoma: lessons learned from bench to bedside.
Phosphatidyl-inositol-3 kinases (PI3Ks) constitute a family of intracellular lipid kinases that are frequently hyperactivated in glioblastoma. The PI3K complex links growth factor signaling with cellular proliferation, differentiation, metabolism, and survival. Mammalian target of rapamycin (mTOR) acts both as a downstream effector and upstream regulator of PI3K, thus highlighting its importance in glioblastoma. This review highlights laboratory and clinical evidence of mTOR's role in glioblastoma. Mechanisms of escape from mTOR inhibition are also discussed, as well as future clinical strategies of mTOR inhibition.
Akhavan
David
D
The David Geffen UCLA School of Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095-1732, USA.
Cloughesy
Timothy F
TF
Mischel
Paul S
PS
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
D047908:Intracellular Signaling Peptides and Proteins; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases
Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):860-8
16467100
Cancer Cell. 2002 Apr;1(3):269-77
12086863
Cell Cycle. 2010 Jan 15;9(2):211-2
20023392
Cell Metab. 2008 May;7(5):456-65
18460336
Cancer Res. 2002 Sep 1;62(17):5027-34
12208757
Nature. 2008 Oct 23;455(7216):1061-8
18772890
Nat Rev Cancer. 2003 Jan;3(1):11-22
12509763
PLoS Med. 2008 Jan 22;5(1):e8
18215105
Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12867-72
17646646
Cancer Res. 2007 Dec 15;67(24):11712-20
18089801
Clin Cancer Res. 2002 May;8(5):1100-6
12006525
Science. 2007 Oct 12;318(5848):287-90
17872411
PLoS Genet. 2009 Feb;5(2):e1000374
19214224
J Natl Cancer Inst. 2005 Jun 15;97(12):880-7
15956649
Cancer Cell. 2002 Mar;1(2):157-68
12086874
Sci Signal. 2009 Jan 27;2(55):ra4
19176518
Genes Dev. 2009 Jul 15;23(14):1619-24
19605683
Mol Cell. 2008 Apr 25;30(2):214-26
18439900
Cancer Res. 2008 Aug 15;68(16):6516-23
18701474
Cancer Res. 2001 Sep 15;61(18):6674-8
11559533
Nature. 2004 Mar 18;428(6980):332-7
15029198
Nat Rev Cancer. 2002 Jul;2(7):489-501
12094235
J Clin Invest. 2008 Sep;118(9):3065-74
18725988
PLoS Biol. 2007 Apr;5(4):e95
17407381
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10320-5
11504907
Neurology. 2006 Jul 11;67(1):156-8
16832099
Cancer Res. 2006 Aug 15;66(16):7864-9
16912159
Science. 2008 Sep 26;321(5897):1807-12
18772396
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10314-9
11504908
Neoplasia. 2005 Apr;7(4):356-68
15967113
Mol Cell. 2009 Jan 30;33(2):237-47
19187764
Cancer Res. 2003 Apr 1;63(7):1589-95
12670909
Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12932-7
19625624
Invest New Drugs. 2005 Aug;23(4):357-61
16012795
Endocr Relat Cancer. 2001 Sep;8(3):249-58
11566616
Cancer Res. 2005 Jun 15;65(12):5172-80
15958561
J Biol Chem. 1997 Jan 31;272(5):2927-35
9006938
Cancer Cell. 2009 Jul 7;16(1):44-54
19573811
Genes Dev. 2007 Nov 1;21(21):2683-710
17974913
Nature. 2002 Jun 27;417(6892):949-54
12068308
Nat Rev Cancer. 2009 Aug;9(8):563-75
19629071
Cancer Res. 2003 Mar 1;63(5):1106-13
12615729
Nat Med. 2004 Jun;10(6):594-601
15156201
J Clin Invest. 2007 Mar;117(3):730-8
17290308
J Neurooncol. 2010 Jan;96(2):219-30
19562254
PLoS Biol. 2009 Jan 20;7(1):e17
19166270
Oncogene. 2006 Oct 16;25(48):6436-46
17041628
J Biol Chem. 1995 Dec 22;270(51):30562-6
8530489
Circ Res. 2007 Mar 2;100(4):564-71
17272808
J Clin Oncol. 2005 Aug 10;23(23):5294-304
15998902
Cancer Res. 1997 Sep 15;57(18):4130-40
9307304
J Neurooncol. 2009 Mar;92(1):99-105
19018475
Brain Pathol. 2009 Jan;19(1):112-20
19076776
Cancer Res. 2002 Dec 15;62(24):7291-7
12499272
Curr Biol. 1997 Apr 1;7(4):261-9
9094314
Cancer Res. 2006 Feb 1;66(3):1500-8
16452206
Cancer Res. 2003 Jun 1;63(11):2742-6
12782577
Cell. 2003 Nov 26;115(5):577-90
14651849
Mol Cancer Ther. 2009 Apr;8(4):742-53
19372546
Nat Rev Cancer. 2006 Sep;6(9):729-34
16915295
Cancer Res. 2009 Apr 15;69(8):3256-61
19351834
Cell. 2009 May 29;137(5):873-86
19446321
Cancer Cell. 2006 May;9(5):341-9
16697955
Nature. 2006 May 25;441(7092):475-82
16598206
Curr Opin Genet Dev. 2007 Feb;17(1):31-9
17208430
Br J Cancer. 2009 Jan 27;100(2):370-5
19165201
N Engl J Med. 2005 Nov 10;353(19):2012-24
16282176
Sci Signal. 2009 Dec 15;2(101):ra82
20009104
Cancer Res. 2007 Sep 1;67(17):7960-5
17804702
Science. 2005 Feb 18;307(5712):1098-101
15718470
Clin Cancer Res. 2008 Jan 15;14(2):488-93
18223223
Nat Med. 2009 Jan;15(1):110-6
19122659
Mol Cancer Ther. 2007 Mar;6(3):1167-74
17363510
Mol Cancer Ther. 2008 Jul;7(7):1851-63
18606717
J Biol Chem. 2009 Mar 20;284(12):8023-32
19150980
N Engl J Med. 2005 Mar 10;352(10):987-96
15758009
Nat Rev Genet. 2006 Aug;7(8):606-19
16847462
Nat Rev Genet. 2001 Feb;2(2):120-9
11253051
Sci Signal. 2009 Apr 21;2(67):pe24
19383975
Cancer Res. 2003 Dec 1;63(23):8132-7
14678966