mTORC1 and mTORC2 in cancer and the tumor microenvironment

被引：349

作者：

Kim, L. C. ^{[1
]}

Cook, R. S. ^{[1
,2
]}

Chen, J. ^{[1
,2
,3
,4
,5
]}

机构：

[1] Vanderbilt Univ, Dept Canc Biol, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Dept Med, Div Rheumatol & Immunol, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Dept Cell & Dev Biol, Nashville, TN 37232 USA

[5] Tennessee Valley Healthcare Syst, Vet Affairs Med Ctr, Nashville, TN USA

来源：

ONCOGENE | 2017年 / 36卷 / 16期

关键词：

ADVANCED SOLID TUMORS; I DOSE-ESCALATION; TRANSFER-RNA SYNTHETASE; P70; S6; KINASE; PHASE-I; MAMMALIAN TARGET; PI3K/MTOR INHIBITOR; TUBEROUS SCLEROSIS; COMPLEX; PHOSPHOPROTEOME REVEALS;

D O I：

10.1038/onc.2016.363

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The mammalian target of rapamycin (mTOR) is a crucial signaling node that integrates environmental cues to regulate cell survival, proliferation and metabolism, and is often deregulated in human cancer. mTOR kinase acts in two functionally distinct complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), whose activities and substrate specificities are regulated by complex co-factors. Deregulation of this centralized signaling pathway has been associated with a variety of human diseases including diabetes, neurodegeneration and cancer. Although mTORC1 signaling has been extensively studied in cancer, recent discoveries indicate a subset of human cancers harboring amplifications in mTORC2-specific genes as the only actionable genomic alterations, suggesting a distinct role for mTORC2 in cancer as well. This review will summarize recent advances in dissecting the relative contributions of mTORC1 versus mTORC2 in cancer, their role in tumor-associated blood vessels and tumor immunity, and provide an update on mTOR inhibitors.

引用

页码：2191 / 2201

页数：11

共 143 条

[1] mTOR regulates memory CD8 T-cell differentiation [J].

Araki, Koichi ;

Turner, Alexandra P. ;

Shaffer, Virginia Oliva ;

Gangappa, Shivaprakash ;

Keller, Susanne A. ;

Bachmann, Martin F. ;

Larsen, Christian P. ;

Ahmed, Rafi .

NATURE, 2009, 460 (7251) :108-U124

[2] STRUCTURAL BIOLOGY Architecture of human mTOR complex 1 [J].

Aylett, Christopher H. S. ;

Sauer, Evelyn ;

Imseng, Stefan ;

Boehringer, Daniel ;

Hall, Michael N. ;

Ban, Nenad ;

Maier, Timm .

SCIENCE, 2016, 351 (6268) :48-52

[3] FOXO3a is activated in response to hypoxic stress and inhibits HiF1-induced apoptosis via regulation of CITED2 [J].

Bakker, Walbert J. ;

Harris, Isaac S. ;

Mak, Tak W. .

MOLECULAR CELL, 2007, 28 (06) :941-953

[4] Molecular Profiling of the Residual Disease of Triple-Negative Breast Cancers after Neoadjuvant Chemotherapy Identifies Actionable Therapeutic Targets [J].

Balko, Justin M. ;

Giltnane, Jennifer M. ;

Wang, Kai ;

Schwarz, Luis J. ;

Young, Christian D. ;

Cook, Rebecca S. ;

Owens, Phillip ;

Sanders, Melinda E. ;

Kuba, Maria G. ;

Sanchez, Violeta ;

Kurupi, Richard ;

Moore, Preston D. ;

Pinto, Joseph A. ;

Doimi, Franco D. ;

Gomez, Henry ;

Horiuchi, Dai ;

Goga, Andrei ;

Lehmann, Brian D. ;

Bauer, Joshua A. ;

Pietenpol, Jennifer A. ;

Ross, Jeffrey S. ;

Palmer, Gary A. ;

Yelensky, Roman ;

Cronin, Maureen ;

Miller, Vincent A. ;

Stephens, Phillip J. ;

Arteaga, Carlos L. .

CANCER DISCOVERY, 2014, 4 (02) :232-245

[5] First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014 [J].

Basu, Bristi ;

Dean, Emma ;

Puglisi, Martina ;

Greystoke, Alastair ;

Ong, Michael ;

Burke, Wendy ;

Cavallin, Maria ;

Bigley, Graham ;

Womack, Christopher ;

Harrington, Elizabeth A. ;

Green, Stephen ;

Oelmann, Elisabeth ;

de Bono, Johann S. ;

Ranson, Malcolm ;

Banerji, Udai .

CLINICAL CANCER RESEARCH, 2015, 21 (15) :3412-3419

[6] mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle [J].

Ben-Sahra, Issam ;

Hoxhaj, Gerta ;

Ricoult, Stephane J. H. ;

Asara, John M. ;

Manning, Brendan D. .

SCIENCE, 2016, 351 (6274) :728-733

[7] Stimulation of de Novo Pyrimidine Synthesis by Growth Signaling Through mTOR and S6K1 [J].

Ben-Sahra, Issam ;

Howell, Jessica J. ;

Asara, John M. ;

Manning, Brendan D. .

SCIENCE, 2013, 339 (6125) :1323-1328

[8] A Phase I Dose-Escalation Study to Assess Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of the Dual mTORC1/mTORC2 Kinase Inhibitor CC-223 in Patients With Advanced Solid Tumors or Multiple Myeloma [J].

Bendell, Johanna C. ;

Kelley, Robin K. ;

Shih, Kent C. ;

Grabowsky, Jennifer A. ;

Bergsland, Emily ;

Jones, Suzanne ;

Martin, Thomas ;

Infante, Jeffrey R. ;

Mischel, Paul S. ;

Matsutani, Tomoo ;

Xu, Shuichan ;

Wong, Lilly ;

Liu, Yong ;

Wu, Xiaoling ;

Mortensen, Deborah S. ;

Chopra, Rajesh ;

Hege, Kristen ;

Munster, Pamela N. .

CANCER, 2015, 121 (19) :3481-3490

[9] A phase Ib study of linsitinib (OSI-906), a dual inhibitor of IGF-1R and IR tyrosine kinase, in combination with everolimus as treatment for patients with refractory metastatic colorectal cancer [J].

Bendell, Johanna C. ;

Jones, Suzanne F. ;

Hart, Lowell ;

Spigel, David R. ;

Lane, Cassie M. ;

Earwood, Chris ;

Infante, Jeffrey R. ;

Barton, John ;

Burris, Howard A. .

INVESTIGATIONAL NEW DRUGS, 2015, 33 (01) :187-193

[10] Rapamycin passes the torch: a new generation of mTOR inhibitors [J].

Benjamin, Don ;

Colombi, Marco ;

Moroni, Christoph ;

Hall, Michael N. .

NATURE REVIEWS DRUG DISCOVERY, 2011, 10 (11) :868-880

← 1 2 3 4 5 6 7 8 9 10 →