Targeting mTOR signaling in lung cancer

Marinov, Marin; Fischer, Barbara; Arcaro, Alexandre

doi:10.1016/j.critrevonc.2007.04.002

Cited by 63 publications

(60 citation statements)

References 137 publications

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“…mTOR is also one of the main downstream effectors in the PI3K/AKT pathway that is critically involved in the mediation of cell survival (12)(13)(14). This pathway is aberrantly activated in several different tumor models (13,14,16,17). Due to these functions, mTOR has been regarded as an attractive target of anticancer agents; the functions of mTOR are blocked by rapamycin, as well as by other mTOR inhibitors, such as everolimus and temsirolimus (23).…”

Section: Discussionmentioning

confidence: 99%

“…Both AKT and mTOR are activated through phosphorylation of specific amino acid residues (15). The AKT/mTOR signaling pathway is aberrantly activated in many tumor types (13,14,16,17). In particular, this pathway seems to play a role in tumor cell growth and proliferation in human pulmonary carcinoid cells (18,19), as well in small-cell lung cancer cells (12,20).…”

Section: Introductionmentioning

confidence: 99%

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Expression of p-AKT and p-mTOR in a large series of bronchopulmonary neuroendocrine tumors

Alì

Boldrini

Capodanno

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Bronchopulmonary neuroendocrine tumors (BP-NETs) are separated into four subgroups: typical carcinoid tumor (TC), atypical carcinoid tumor (AC), large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung carcinoma (SCLC). The signaling pathway involving AKT/ mammalian target of rapamycin (mTOR) is crucial to the regulation of cell growth, proliferation and survival, and is frequently activated in human cancers. Consequently, mTOR is considered an attractive target for anticancer agents. The present study aimed to evaluate the expression of phosphorylated AKT and mTOR in a series of BP-NETs, and to analyze the correlations with clinicopathological parameters. p-AKT and p-mTOR levels were determined by immunohistochemistry in a series of 210 BP-NETs, including 85 SCLCs, 17 LCNECs, 26 ACs, 75 TCs and 7 tumorlets. Higher p-AKT and p-mTOR expression levels were identified in the majority of tumorlets and carcinoids in comparison to the LCNECs (P=0.0001) and SCLCs (P=0.0002). Furthermore, a significant association was observed between p-mTOR expression and tumor size (T) in SCLCs (P=0.04) and LCNECs (P=0.03): T3-T4 tumors exhibited significantly lower p-mTOR expression compared to T1-T2 tumors. In conclusion, most of the BP-NETs examined in this study expressed p-AKT and p-mTOR, suggesting that the AKT/mTOR pathway plays an important role in these tumors. Additionally, our results confirm that low-to intermediate-grade tumors are more closely associated to each other than to high-grade tumors, despite sharing common classification and a common origin from neuroendocrine cells. These findings improve our knowledge of the biological characterization of these tumors and indicate new therapeutic opportunities for the treatment of BP-NETs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression of p-AKT and p-mTOR in a large series of bronchopulmonary neuroendocrine tumors

Alì

Boldrini

Capodanno

et al. 2011

Experimental and Therapeutic Medicine

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“…Conversely, dysregulation of mammalian target of rapamycin (mTOR), a major negative regulator of autophagy, is frequently observed in cancer. Thus, mTOR inhibition has been proposed recently as a strategy for cancer therapy (Marinov et al, 2007). Clinical data suggest that mTOR inhibitors may induce tumor regression in some patients (Dancey, 2005;Panwalkar et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Targeting the Autophagy Pathway Using Ectopic Expression of Beclin 1 in Combination with Rapamycin in Drug-Resistant v-Ha-ras-Transformed NIH 3T3 Cells

Eum

Lee

2011

Molecules and Cells

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“…However, deregulation of the AKTdependent pathway has been well documented in a variety of human tumors [12] and has been associated with resistance to EGFR TKIs in NSCLC cell lines [13]. Deregulation of the PI3K/AKT/mTOR pathway could result from several alterations, including PI3K isoform gene amplification, activating mutations of PI3K subunits, AKT gene amplification and overexpression, as well as loss of function of PTEN [8,14]. Frequent AKT activation and mTOR phosphorylation were found in 51% of NSCLC patients and in 74% of NSCLC cell lines [15].…”

Section: Introductionmentioning

confidence: 99%

Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

Monica

Galetti

Alfieri

et al. 2009

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 ABSTRACTThe epidermal growth factor receptor (EGFR) is a validated target for therapy in non-small cell lung cancer (NSCLC). Most patients, however, either do not benefit or develop resistance to specific inhibitors of the EGFR tyrosine kinase activity, such as gefitinib or erlotinib. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation and survival pathways and has been associated with resistance to EGFR tyrosine kinase inhibitors. In this study, we assessed the effects of combining the mTOR inhibitor everolimus (RAD001) with gefitinib on a panel of NSCLC cell lines characterized by gefitinib-resistance and able to maintain pS6K phosphorylation after gefitinib treatment.Everolimus plus gefitinib induced a significant decrease in the activation of MAPK and mTOR signaling pathways downstream of EGFR and resulted in a growth-inhibitory effect rather than in an enhancement of cell death. A synergistic effect was observed in those cell lines characterized by high proliferative index and low doubling time. These data suggest that treatment with everolimus and gefitinib might be of value in the treatment of selected NSCLC patients that exhibit high tumor proliferative activity.

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Targeting mTOR signaling in lung cancer

Cited by 63 publications

References 137 publications

Expression of p-AKT and p-mTOR in a large series of bronchopulmonary neuroendocrine tumors

Expression of p-AKT and p-mTOR in a large series of bronchopulmonary neuroendocrine tumors

Targeting the Autophagy Pathway Using Ectopic Expression of Beclin 1 in Combination with Rapamycin in Drug-Resistant v-Ha-ras-Transformed NIH 3T3 Cells

Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

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