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• W2056572092 abstract "The mammalian target of rapamycin (mTOR), a 289 kD serine/threonine kinase, belongs to the phosphatidylinositol kinase-related kinase family. It plays a central role in regulating cell growth, proliferation, and survival, in part by regulation of translation initiation.1Bjornsti MA Houghton PJ The TOR pathway: A target for cancer therapy.Natl Rev Cancer. 2004; 4: 335-348Crossref PubMed Scopus (1166) Google Scholar, 2Sawyers CL Will mTOR inhibitors make it as cancer drugs?.Cancer Cell. 2003; 4: 343-348Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 3Hay N Sonenberg N Upstream and downstream of mTOR.Genes Dev. 2004; 18: 1926-1945Crossref PubMed Scopus (3244) Google Scholar In response to mitogen or nutrient stimulation, mTOR regulates translation initiation, primarily through two distinct pathways: ribosomal p70 S6 kinase (p70S6K) and eukaryotic translation initiation factor 4E (eIF4E) binding proteins (4E-BPs). Activated p70S6K by mTOR further phosphorylates the 40S ribosomal protein S6, leading to enhancement of the translation of mRNAs. In addition, mTOR also directly phosphorylates 4E-BP1, which triggers additional phosphorylation events that cause phosphorylated 4E-BP1 to dissociate from eIF4E, thereby increasing the cap-dependent translation of mRNAs, such as cyclin D1 and c-Myc (Fig. 1).1Bjornsti MA Houghton PJ The TOR pathway: A target for cancer therapy.Natl Rev Cancer. 2004; 4: 335-348Crossref PubMed Scopus (1166) Google Scholar, 2Sawyers CL Will mTOR inhibitors make it as cancer drugs?.Cancer Cell. 2003; 4: 343-348Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 3Hay N Sonenberg N Upstream and downstream of mTOR.Genes Dev. 2004; 18: 1926-1945Crossref PubMed Scopus (3244) Google Scholar Therefore, phospho-p70S6K (or phospho-S6) and phospho-4E-BP1 are common read-outs of the mTOR signaling. The PI-3 kinase (PI3K)/Akt signaling represents a major cell survival pathway. Its activation has long been associated with malignant transformation and apoptotic resistance.4Vivanco I Sawyers CL The phosphatidylinositol 3-Kinase AKT pathway in human cancer.Natl Rev Cancer. 2002; 2: 489-501Crossref PubMed Scopus (4897) Google Scholar It is generally thought that mTOR functions downstream of the PI3K/Akt pathway and is phosphorylated (or activated) in response to stimuli that activate the PI3K/Akt pathway (Fig. 1).1Bjornsti MA Houghton PJ The TOR pathway: A target for cancer therapy.Natl Rev Cancer. 2004; 4: 335-348Crossref PubMed Scopus (1166) Google Scholar, 3Hay N Sonenberg N Upstream and downstream of mTOR.Genes Dev. 2004; 18: 1926-1945Crossref PubMed Scopus (3244) Google Scholar In addition to positive regulation of the mTOR axis by PI3K/Akt, recent evidence has linked LKB1, a serine/threonine kinase with tumor suppression activity, to the negative regulation of the mTOR axis.5Shaw RJ Bardeesy N Manning BD et al.The LKB1 tumor suppressor negatively regulates mTOR signaling.Cancer Cell. 2004; 6: 91-99Abstract Full Text Full Text PDF PubMed Scopus (837) Google Scholar It has been proposed that, in response to cellular energy stress, AMP-activated protein kinase (AMPK) is activated through LKB1-mediated phosphorylation and then phosphorylates TSC2 (or tuberin) to enhance TSC2 function. TSC2 subsequently inhibits mTOR function via TSC2’s GAP activity toward the Rheb small GTPase (Fig. 1).6Inoki K Li Y Zhu T Wu J Guan KL TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling.Nat Cell Biol. 2002; 4: 648-657Crossref PubMed Scopus (2234) Google Scholar Under normal conditions, LKB1/AMPK activation overrides the mitogenic signal from Akt and tightly controls mTOR signaling. However, in the absence of LKB1, AMPK cannot be activated, nor can mTOR be inactivated, in response to cellular energy stress.4Vivanco I Sawyers CL The phosphatidylinositol 3-Kinase AKT pathway in human cancer.Natl Rev Cancer. 2002; 2: 489-501Crossref PubMed Scopus (4897) Google Scholar, 7Corradetti MN Inoki K Bardeesy N DePinho RA Guan KL Regulation of the TSC pathway by LKB1: Evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome.Genes Dev. 2004; 18: 1533-1538Crossref PubMed Scopus (445) Google Scholar PI3K/Akt is one of the best characterized pathways downstream of the Ras oncogene.8Downward J Targeting RAS signaling pathways in cancer therapy.Natl Rev Cancer. 2003; 3: 11-22Crossref PubMed Scopus (2337) Google Scholar Because of mutation and overexpression of growth factors and/or their receptors, the Ras signaling pathway is frequently activated in human non-small cell lung cancer (NSCLC).9Mitsuuchi Y Testa JR Cytogenetics and molecular genetics of lung cancer.Am J Med Genet. 2002; 115: 183-188Crossref PubMed Scopus (50) Google Scholar, 10Sekido Y Fong KM Minna JD Molecular genetics of lung cancer.Annu Rev Med. 2003; 54: 73-87Crossref PubMed Scopus (262) Google Scholar, 11Hirsch FR Scagliotti GV Langer CJ Varella-Garcia M Franklin WA Epidermal growth factor family of receptors in preneoplasia and lung cancer: perspectives for targeted therapies.Lung Cancer. 2003; 41: S29-S42Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar As a result, the PI3/Akt pathway is also frequently activated in human NSCLC, as demonstrated in several studies.12Brognard J Clark AS Ni Y Dennis PA Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation.Cancer Res. 2001; 61: 3986-3997PubMed Google Scholar, 13Lee SH Kim HS Park WS et al.Non-small cell lung cancers frequently express phosphorylated Akt; an immunohistochemical study.APMIS. 2002; 110: 587-592Crossref PubMed Scopus (96) Google Scholar, 14Balsara BR Pei J Mitsuuchi Y et al.Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions.Carcinogenesis. 2004; 25: 2053-2059Crossref PubMed Scopus (236) Google Scholar, 15Tsao AS McDonnell T Lam S et al.Increased phospho-AKT [Ser(473)] expression in bronchial dysplasia: Implications for lung cancer prevention studies.Cancer Epidemiol Biomarkers Prev. 2003; 12: 660-664PubMed Google Scholar, 16David O Jett J LeBeau H et al.Phospho-Akt overexpression in non-small cell lung cancer confers significant stage-independent survival disadvantage.Clin Cancer Res. 2004; 10: 6865-6871Crossref PubMed Scopus (169) Google Scholar Although somatic LKB1 mutations are rare in most sporadic tumor types,17Avizienyte E Loukola A Roth S et al.LKB1 somatic mutations in sporadic tumors.Am J Pathol. 1999; 154: 677-681Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 18Avizienyte E Roth S Loukola A et al.Somatic mutations in LKB1 are rare in sporadic colorectal and testicular tumors.Cancer Res. 1998; 58: 2087-2090PubMed Google Scholar there is a high frequency of LKB1 mutations in human NSCLC, particularly adenocarcinomas. It has been reported that LKB1 gene alterations were present in 54% of lung adenocarcinoma cell lines and in approximately 30% of primary lung adenocarcinomas.19Sanchez-Cespedes M Parrella P Esteller M et al.Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung.Cancer Res. 2002; 62: 3659-3662PubMed Google Scholar, 20Carretero J Medina PP Pio R Montuenga LM Sanchez-Cespedes M Novel and natural knockout lung cancer cell lines for the LKB1/STK11 tumor suppressor gene.Oncogene. 2004; 23: 4037-4040Crossref PubMed Scopus (103) Google Scholar Thus, it seems that LKB1 inactivation is a critical event in the development of sporadic lung adenocarcinomas. Because of the constitutive activation of PI3K/Akt signaling and frequent mutations or inactivation of the LKB1 gene, it is likely that the mTOR axis is dysregulated and activated in human NSCLC, particularly adenocarcinomas. Indeed, a recent report by Balsara et al.14Balsara BR Pei J Mitsuuchi Y et al.Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions.Carcinogenesis. 2004; 25: 2053-2059Crossref PubMed Scopus (236) Google Scholar indicates that phosphorylation or activation of mTOR was detected in 74% of NSCLC, which was significantly associated with activation of Akt. Therefore, the mTOR signaling axis represents a highly promising therapeutic target for lung cancer therapy. Rapamycin and its derivatives CCI-779 and RAD001 are novel anticancer drugs developed to modulate mTOR activation.1Bjornsti MA Houghton PJ The TOR pathway: A target for cancer therapy.Natl Rev Cancer. 2004; 4: 335-348Crossref PubMed Scopus (1166) Google Scholar, 3Hay N Sonenberg N Upstream and downstream of mTOR.Genes Dev. 2004; 18: 1926-1945Crossref PubMed Scopus (3244) Google Scholar Our studies have shown that rapamycin is effective in inhibiting the growth of human NSCLC cells.21Sun SY Rosenberg LM Wang X et al.Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition.Cancer Res. 2006; 65: 7052-7058Crossref Scopus (678) Google Scholar In animal models, rapamycin effectively inhibited the growth of a NSCLC tumor22Boffa DJ Luan F Thomas D et al.Rapamycin inhibits the growth and metastatic progression of non-small cell lung cancer.Clin Cancer Res. 2004; 10: 293-300Crossref PubMed Scopus (87) Google Scholar and alveolar epithelial neoplasia induced by oncogenic K-Ras.23Wislez M Spencer ML Izzo JG et al.Inhibition of mammalian target of rapamycin reverses alveolar epithelial neoplasia induced by oncogenic K-ras.Cancer Res. 2006; 65: 3226-3235Google Scholar Several recent studies have shown that an mTOR inhibitor such as RAD001 sensitizes cancer cells to chemotherapy,24Beuvink I Boulay A Fumagalli S et al.The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation.Cell. 2006; 120: 747-759Abstract Full Text Full Text PDF Scopus (434) Google Scholar, 25Mondesire WH Jian W Zhang H et al.Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells.Clin Cancer Res. 2004; 10: 7031-7042Crossref PubMed Scopus (278) Google Scholar radiation,26Shinohara ET Cao C Niermann K et al.Enhanced radiation damage of tumor vasculature by mTOR inhibitors.Oncogene. 2006; 24: 5414-5422Crossref Scopus (167) Google Scholar or overcomes chemoresistance27Wu C Wangpaichitr M Feun L Kuo MT Robles C Lampidis T Savaraj N Overcoming cisplatin resistance by mTOR inhibitor in lung cancer.Mol Cancer. 2005; 4: 25Crossref PubMed Scopus (104) Google Scholar in several types of cancer cells, including lung cancer cells. Our unpublished data also show that the combination of rapamycin and docetaxel is synergistic in inhibiting the growth of lung cancer cells. Therefore, we postulate that mTOR inhibitors, like other signal transduction inhibitors, could be more efficacious if used in combination with other agents or therapies, such as chemotherapy or other targeted agents in lung cancer treatment, as long as these combinations are based on sound preclinical and clinical drug development principles. Our recent data clearly show that mTOR inhibition by rapamycin triggers rapid and sustained activation of PI3K/Akt survival pathway, in human lung and other types of cancer cells.21Sun SY Rosenberg LM Wang X et al.Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition.Cancer Res. 2006; 65: 7052-7058Crossref Scopus (678) Google Scholar Thus, one rational approach for mTOR-targeted lung cancer therapy is to use an mTOR inhibitor in combination with a drug that blocks PI3K/Akt activation such as a PI3K inhibitor, as we demonstrated in our study.21Sun SY Rosenberg LM Wang X et al.Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition.Cancer Res. 2006; 65: 7052-7058Crossref Scopus (678) Google Scholar This study supported by the Winship Cancer Institute faculty start-up research fund (to SYS), the Georgia Cancer Coalition Distinguished Cancer Scholar award (to SYS), Department of Defense IMPACT grant W81XWH-05-0027 (to FRK and SYS), and the Georgia Cancer Coalition Research Award (to HF). SYS and FRK are Georgia Cancer Coalition Distinguished Cancer Scholars." @default.
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• W2056572092 title "Targeting mTOR Signaling for Lung Cancer Therapy" @default.
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