Enhancing mTOR-targeted cancer therapy.
BACKGROUND
The mammalian target of rapamycin (mTOR) has emerged as an attractive cancer therapeutic target. Accordingly, several mTOR inhibitors (e.g., rapamycin and its analogs; rapalogs) are currently being tested in many cancer clinical trials. Despite the encouraging results showing that some rapalogs improved overall survival among patients with metastatic renal-cell carcinoma, the single-agent activity of rapalogs in most other tumor-types has been modest, at best.


OBJECTIVE
To review the current understanding of the mTOR axis and discuss potential strategies to enhance mTOR-targeted cancer therapy.


METHODS
Preclinical and clinical data in peer-reviewed reports on the novel biological and therapeutic parts of the mTOR axis are discussed.


CONCLUSIONS
The mTOR axis involves complex regulatory networks. Inhibition of the mTOR axis with a rapalog induces feedback activation of several survival signaling pathways such as Akt activation, which, in turn, blunt rapalogs' anticancer efficacy. Thus, blockage or prevention of the activation of these survival signaling pathways may enhance mTOR-targeted cancer therapy.
Wang
Xuerong
X
Emory University School of Medicine, Winship Cancer Institute, Department of Hematology, Atlanta, GA 30322, USA.
Sun
Shi-Yong
SY
D000970:Antineoplastic Agents / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
J Hepatol. 2008 Dec;49(6):985-97
18930332
Oncogene. 2004 Apr 19;23(18):3180-8
15094767
Nature. 2006 May 25;441(7092):424-30
16724053
Biochem Pharmacol. 2008 Mar 1;75(5):1035-44
18191814
Mol Cell Biol. 2008 Jun;28(12):4104-15
18411301
Oncogene. 2004 May 13;23(22):4037-40
15021901
Science. 2005 Feb 18;307(5712):1098-101
15718470
Trends Biochem Sci. 2004 Jan;29(1):18-24
14729328
Cancer Biol Ther. 2008 Dec;7(12):1952-8
18981735
Biochem Soc Trans. 2009 Feb;37(Pt 1):217-22
19143635
Mol Cell Biol. 2002 Mar;22(6):1656-63
11865045
Int J Biochem Cell Biol. 2008;40(12):2675-80
18069043
Nat Rev Cancer. 2002 Jul;2(7):529-35
12094239
Br J Cancer. 2006 Nov 6;95(9):1148-54
17031397
Oncogene. 2004 Apr 19;23(18):3172-9
15094766
J Cell Biol. 2004 Nov 8;167(3):399-403
15533996
Drug Resist Updat. 2008 Feb-Apr;11(1-2):32-50
18166498
Cancer Res. 2007 Dec 1;67(23):11300-8
18056456
Mol Cell Biol. 2007 Nov;27(21):7405-13
17724079
Dev Cell. 2006 Dec;11(6):859-71
17141160
Biochem Pharmacol. 2000 Oct 15;60(8):1237-43
11007962
Clin Exp Metastasis. 2004;21(6):477-83
15679045
Trends Biochem Sci. 2005 Jan;30(1):35-42
15653324
Biochim Biophys Acta. 2009 Sep;1791(9):949-55
19264150
Nat Cell Biol. 2007 Mar;9(3):316-23
17277771
EMBO J. 2008 Jul 23;27(14):1919-31
18566587
J Clin Invest. 2008 Sep;118(9):3065-74
18725988
Curr Biol. 2008 Sep 9;18(17):1269-77
18722121
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10314-9
11504908
PLoS Biol. 2009 Feb 10;7(2):e38
19209957
Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8286-91
18550814
Cancer Res. 2005 Aug 15;65(16):7052-8
16103051
Science. 2001 Nov 30;294(5548):1942-5
11729323
EMBO J. 2008 Jul 23;27(14):1932-43
18566586
Oncogene. 2007 Dec 13;26(57):7825-32
17599048
Oncogene. 2007 Mar 22;26(13):1932-40
17001314
Genes Dev. 2004 Aug 15;18(16):1926-45
15314020
Cancer Res. 2008 Feb 1;68(3):631-4
18245460
Mol Cancer Ther. 2006 Oct;5(10):2494-502
17041093
J Clin Oncol. 2008 Apr 1;26(10):1603-10
18332469
Clin Cancer Res. 2008 Jun 15;14(12):3993-4001
18559622
Cancer Cell. 2004 Jul;6(1):91-9
15261145
J Biol Chem. 2007 Aug 24;282(34):24514-24
17604271
Cancer. 2009 Jun 1;115(11):2438-46
19306412
Cancer Cell. 2007 Jul;12(1):9-22
17613433
Cancer Res. 2007 Aug 1;67(15):7106-12
17671177
Anticancer Drugs. 2009 Apr;20(4):259-66
19240643
Eur J Cancer. 2005 Nov;41(17):2754-9
16246546
Sci Signal. 2009 Apr 21;2(67):pe27
19383978
Neoplasia. 2005 Oct;7(10):921-9
16242075
BMC Cancer. 2009 May 27;9:161
19473483
Blood. 2007 Apr 15;109(8):3509-12
17179228
J Clin Invest. 2007 Mar;117(3):730-8
17290308
Prog Mol Subcell Biol. 2001;27:132-42
11575158
Mol Cell. 2007 Mar 23;25(6):903-15
17386266
Cancer Cell. 2006 Feb;9(2):77-9
16473275
Cancer Biol Ther. 2007 Feb;6(2):195-201
17218776
Cancer Res. 2007 Oct 1;67(19):9006-12
17909001
Cell Death Differ. 2007 Dec;14(12):2085-94
17932503
Br J Cancer. 2008 Mar 11;98(5):923-30
18319715
Int J Biochem Cell Biol. 1999 Jan;31(1):43-57
10216943
Nat Cell Biol. 2002 Sep;4(9):648-57
12172553
J Biol Chem. 2008 Jun 6;283(23):15619-27
18372248
Mol Cancer Ther. 2006 Nov;5(11):2676-84
17121914
J Mol Med (Berl). 2007 Jul;85(7):707-21
17571248
Genes Dev. 2007 Dec 15;21(24):3232-7
18055695
Nat Rev Cancer. 2004 May;4(5):335-48
15122205
Cancer Res. 2006 Feb 1;66(3):1500-8
16452206
Cancer Res. 2004 Dec 1;64(23):8639-42
15574771
Leuk Res. 2007 May;31(5):673-82
17007924
J Biol Chem. 2007 Jul 13;282(28):20329-39
17517883
Cell. 2007 Jun 29;129(7):1261-74
17604717
Cancer Res. 2002 Jul 1;62(13):3659-62
12097271
Mol Cancer Ther. 2005 Oct;4(10):1533-40
16227402
Cell. 2009 May 29;137(5):873-86
19446321
Science. 2008 Sep 12;321(5895):1499-502
18787170
Lancet. 2008 Aug 9;372(9637):449-56
18653228
Cancer Res. 2008 Sep 15;68(18):7409-18
18794129
Mol Cell. 2006 Apr 21;22(2):159-68
16603397
Cancer Res. 2009 Aug 1;69(15):6232-40
19584280
N Engl J Med. 2007 May 31;356(22):2271-81
17538086
Cancer Cell. 2006 Mar;9(3):153-5
16530700
Cancer Cell. 2006 May;9(5):341-9
16697955
Cancer Cell. 2004 Jun;5(6):519-23
15193254
Trends Mol Med. 2007 Oct;13(10):433-42
17905659
Cancer Cell. 2009 Feb 3;15(2):148-59
19185849
Biochem J. 2008 Dec 15;416(3):375-85
18925875
Mol Cancer Ther. 2005 Jan;4(1):101-12
15657358
Proc Natl Acad Sci U S A. 2004 Sep 14;101(37):13489-94
15342917
J Biol Chem. 2008 Jul 11;283(28):19201-10
18487207
Mol Cancer Ther. 2008 Jul;7(7):1851-63
18606717
BMC Pharmacol. 2009 Apr 15;9:8
19368729
Cell. 2005 Apr 22;121(2):179-93
15851026
Mol Cell Biol. 2009 Mar;29(6):1411-20
19114562
Curr Biol. 2004 Jul 27;14(14):1296-302
15268862
Nat Rev Mol Cell Biol. 2009 May;10(5):307-18
19339977
J Biol Chem. 2009 Mar 20;284(12):8023-32
19150980
Br J Cancer. 2008 Sep 2;99(5):683-8
18728656
Sci Signal. 2009 Apr 21;2(67):pe24
19383975
Oncogene. 2004 Apr 19;23(18):3189-99
15094768
Clin Cancer Res. 2007 Jun 1;13(11):3109-14
17545512
J Biol Chem. 2007 Jul 6;282(27):20036-44
17510057
Cancer Res. 2009 Mar 1;69(5):1821-7
19244117