The role of mTOR in the management of solid tumors: An overview

• Published in: Cancer treatment reviews Vol. 35; no. 2; pp. 148 - 159
• Main Authors: Strimpakos, Alex S, Karapanagiotou, Eleni M, Saif, M. Wasif, Syrigos, Kostas N
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-04-2009
• Subjects: Akt protein kinase; Animals; Antineoplastic Agents - pharmacology; Carcinogenesis; Hematology, Oncology and Palliative Medicine; Humans; Molecular pathways; mTOR; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; PI3-Kinase; Protein Kinases - chemistry; Protein Kinases - physiology; Rapamycin; Rapamycin analogs; Signal Transduction - physiology; Sirolimus - analogs & derivatives; Sirolimus - pharmacology; Targeted therapy; TOR Serine-Threonine Kinases; retinoblastoma protein; PR; time to progression; DLTs; stable disease; CDK; progression free survival; tuberous sclerosis complex 1 and 2; overall response rate; BSC; maximum tolerated dose; STS; PI3K; PRAS40; bevacizumab; low grade neuroendocrine tumor; PFS; hepatocellular carcinoma; GTPase activating protein; PDK1; colorectal cancer; head and neck squamous cell carcinomas; LOH; mammalian lethal with SEC 13; Huntingtin, EF3, A subunit of PP2A, TOR; SCH66336; S6 protein kinase 1; RCC; Peutz–Jeghers syndrome; TOP; HNSCC; AMPK; mLST8; cyclin-dependent kinase; PIKK; phosphoinositide 3-kinase; mSIN1; PIP 2; clinical benefit response; PIP 3; E; IRS-1; MRI; platelet derived growth factor beta; eukaryotic initiation factor 4E; IGFR; RTK; alanine transferase; FATC; FKB12 rapamycin binding protein; protein kinase C alpha; vascular endothelial factor receptor; Carcinogenesis; phosphatase and tensin homologue deleted on chromosome 10; cholangiocellular carcinoma; SD; mammalian target of rapamycin; glycogen synthase kinase-3; BV; Richtor; Rheb; PI3-Kinase; REDD1/2; loss of heterozygosity; Bannayan–Riley–Ruvalcaba syndrome; phosphatidylinositol kinases; IFN-A; CD; soft tissue sarcomas; SSCP/HD; best supportive care; NSCLC; epidermal growth factor receptor; FKBP12-rapamycin-associated protein; murine double minute 2; dominant rapamycin resistant (gene); deferolimus; CR; Rapamycin analogs; CT; LGNET; mTOR complex 1 and 2; Ras homologue enriched in brain; temsirolimus; FRAP-ATM-TRRAP; MDM2; regulated in development and DNA damage 1 and 2; receptor tyrosine kinase; PI3KKC3; ATP; insulin growth factor receptor; PRR5; FK 506; DRR; proline rich Akt substrate 40 kDa; PTEN; ALT; Forkhead box protein O; initiation of translation factor 4E-BP1; BRRS; fibroblast growth factor; mRCC; mTOR; overall survival; PJS; regulatory associated protein of mTOR; phosphatidylinositol (4,5)-biphosphate; MDT; PKCa; rapamycin insensitive companion of mTOR; non-small cell lung cancer; phosphatidylinositol (3,4,5)-triphosphate; FOXO; pRB; single-strand conformational polymorphism/heteroduplex; FGF; TSC; PKB; HCC; Rapamycin; phosphoinositide-dependent protein kinase1; EV; adenosine monophosphate-dependent protein kinase; CRC; GAP; interferon alpha; RAD001; mammalian stress-activated protein kinase interacting protein 1; mTORC1-2; PI3K class III; glioblastoma multiforme; magnetic resonance imaging; CCI-779; Targeted therapy; fat domain close to the C-terminus; GSK-3; EGFR; ORR; Raptor; PDGFRβ; HEAT; HIF-1; TTP; Molecular pathways; CBR; everolimus; GBM; dose limiting toxicities; FAT domain; farnesyl transferase inhibitor lorafarnib; FRAP; partial response; Cowden’s disease; protein kinase B; computed tomography; insulin growth factor; CCC; eIF4E; OS; 4E binding protein 1; erlotinib; VEGF; Akt protein kinase; complete response; IGF; metastatic renal cell carcinoma; tarcolimus; hypoxia inducible factor 1; S6K1; AP23573; proline rich protein 5; renal cell carcinoma; insulin receptor substrate 1; FRB; terminal oligopyrimidine; 4E-BP1; adenosine 5′-triphosphate; PHAS-I
• ISSN: 0305-7372; 1532-1967
• DOI: 10.1016/j.ctrv.2008.09.006

Summary Mammalian target of rapamycin (mTOR) is a key protein kinase controlling signal transduction from various growth factors and upstream proteins to the level of mRNA and ribosome with a regulatory effect on cell cycle progression, cellular proliferation and growth. TOR genes were discovered rather serendipitously while investigating the cause of resistance to immunosuppressant rapamycin in yeast. In normal cells, mTOR controls brilliantly the load of signals from its effectors resulting in a normal cell function. On the contrary, in various diseases and mainly in cancer this balance is lost due to mutations or overactivation of upstream pathways leading to a persistent proliferation and tumor growth. What makes mTOR attractive to researchers seems to be its key position which is on the crossroad of various signal pathways (Ras, PI3K/Akt, TSC, NF-κB) towards mRNA, ribosome, protein synthesis and translation of significant molecules, the uncontrolled production of which may lead to tumor proliferation and growth. Inhibition of mTOR by rapamycin (a natural product) or its analogs aims to prevent the deleterious effects of the abnormal signaling, regardless at which point of the signal pathway has the abnormality launched. Here, we will review the physiological functions of mTOR, its association to carcinogenesis and the latest evidence regarding the use of mTOR inhibitors in cancer treatment as well as future trends and aims of research.