mTOR Inhibition Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt

O'Reilly, Kathryn E.; Rojo, F.; She, Qing‐Bai; Solit, David B.; Mills, Gordon B.; Smith, Debra L.; Lane, Heidi A.; Hofmann, Francesco; Hicklin, Daniel J.; Ludwig, Dale L.; Baselga, J.; Rosen, Neal

doi:10.1158/0008-5472.can-05-2925

Cited by 2,264 publications

(2,091 citation statements)

References 27 publications

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“…On the other hand, recent investigations showed that mTOR inhibition activates the upstream signaling such as Akt (Shi et al, 2005;O'Reilly et al, 2006). Therefore, we determined whether rapamycin or mTOR siRNA stimulates the phosphorylation of Akt in malignant glioma cells.…”

Section: Enhancement Of the Rapamycin-induced Antitumor Effect On Malmentioning

confidence: 93%

Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

et al. 2006

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The mammalian target of rapamycin (mTOR) plays a central role in regulating the proliferation of malignant glioma cells, and mTOR-specific inhibitors such as rapamycin analogs are considered as promising therapy for malignant gliomas. However, the efficacy of mTOR inhibitors alone in the treatment of patients with malignant gliomas is only modest, potentially because these agents rather than acting as mTOR kinase inhibitors instead interfere with the function of only mTOR/raptor (regulatory-associated protein of mTOR) complex and thus do not perturb all mTOR functions. The purpose of this study was to determine whether global inhibition of the mTOR molecule enhances the antitumor effect of rapamycin on malignant glioma cells. We showed that rapamycin induced autophagy and that inhibition of autophagy by small interfering RNA (siRNA) directed against autophagyrelated gene Beclin 1 attenuated the cytotoxicity of rapamycin in rapamycin-sensitive tumor cells, indicating that the autophagy was a primary mediator of rapamycin's antitumor effect rather than a protective response. Exogenous expression of an mTOR mutant interfering with its kinase activity markedly enhanced the incidence of rapamycin-induced autophagy. Moreover, silencing of mTOR with siRNA augmented the inhibitory effect of rapamycin on tumor cell viability by stimulating autophagy. Importantly, not only rapamycin-sensitive malignant glioma cells with PTEN mutations but also rapamycin-resistant malignant glioma cells with wild-type PTEN were sensitized to rapamycin by mTOR siRNA. These results indicate that rapamycin-induced autophagy is one of the agent's antitumor effects and that silencing or inhibiting mTOR kinase activity could enhance the effectiveness of rapamycin.

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Section: Enhancement Of the Rapamycin-induced Antitumor Effect On Malmentioning

confidence: 93%

Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

et al. 2006

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“…For example, S6K inhibits IRS‐1 at both the transcriptional and protein level. Inhibition of mTORC1 and its downstream target S6K consequently results in relief of this feedback inhibition and reactivation of IRS‐1 (O'Reilly et al ., 2006). Importantly, S6K also inhibits the mTORC2 complex by phosphorylating RICTOR at Thr1135.…”

Section: Introductionmentioning

confidence: 99%

“…Of note, the FBP12/rapalog complex does not inhibit the mTORC2 complex. Consequently, due to relief of the feedback loops described above, rapalogs induce paradoxical activation of AKT (Beauchamp and Platanias, 2013; O'Reilly et al ., 2006). Nevertheless, despite this limitation, everolimus (RAD001, Afinitor) and temsirolimus have clinical activity in advanced renal cell cancers, advanced pancreatic neuroendocrine tumours (PNET) and advanced hormone receptor‐positive/HER2‐negative breast cancers, with everolimus FDA‐approved for the treatment of these tumours (O'Reilly and McSheehy, 2010; Populo et al ., 2012).…”

Section: Introductionmentioning

confidence: 99%

K‐Ras mutation and amplification status is predictive of resistance and high basal pAKT is predictive of sensitivity to everolimus in biliary tract cancer cell lines

et al. 2017

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Advanced biliary tract cancer (BTC) has a poor prognosis and limited treatment options. The PI3K/Akt/mTOR signalling pathway is hyperactivated in a subset of BTCs, and clinical activity of the mTOR inhibitor everolimus has been observed in some patients with BTC. The goal of this study was to identify biomarkers predictive of everolimus response. Twenty BTC cell lines were assessed for everolimus sensitivity with a spectrum of growth inhibitory responses observed. Molecular biomarkers of sensitivity and resistance were identified by interrogation of the activation status of the Ras/MAPK and PI3K/Akt/mTOR pathways. K‐Ras mutations and/or amplifications were identified in 45% of cell lines and were associated with resistance to everolimus. Activating mutations in PIK3CA or loss of PTEN was not predictive of everolimus response; however, high basal levels of pAKT were associated with sensitivity, independent of Ras/MAPK pathway activation status. Notably, everolimus inhibited mTOR signalling to a similar extent in sensitive and resistant cell lines, suggesting that relative dependence on the mTOR pathway rather than the magnitude of pathway inhibition determines everolimus response. Consistent with the known limitations of rapalogs, everolimus induced feedback‐mediated activation of AKT in BTC cell lines, which could be overcome by cotreatment with an AKT inhibitor or ATP‐competitive mTORC1/mTORC2 inhibitors. However, both approaches failed to induce greater apoptosis compared to everolimus, and mTORC1/mTORC2 kinase inhibitors induced compensatory activation of pERK, identifying an inherent limitation of these agents in BTC cell lines. These findings suggest that future trials of everolimus in BTC would benefit from preselecting patients based on their K‐Ras and PI3K/mTOR pathway activation status. The study also identifies strategies for enhancing inhibition of the PI3K/mTOR pathway in BTC cell lines.

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“…It is recognized that mTOR inhibition induces insulin receptor substrate-1 expression and inhibits a normally negative feedback loop resulting in AKT activation in some cancer cell lines [39,42].…”

mentioning

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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mTOR Inhibition Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt

Cited by 2,264 publications

References 27 publications

Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

K‐Ras mutation and amplification status is predictive of resistance and high basal pAKT is predictive of sensitivity to everolimus in biliary tract cancer cell lines

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

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