Dose- and Schedule-Dependent Inhibition of the Mammalian Target of Rapamycin Pathway With Everolimus: A Phase I Tumor Pharmacodynamic Study in Patients With Advanced Solid Tumors

Tabernero, Josep; Rojo, Federico; Calvo, Emiliano; Burris, Howard A.; Judson, Ian; Hazell, Katharine; Martinelli, Erika; Cajal, Santiago Ramón y; Jones, Suzanne F.; Vidal, Laura; Shand, N.; Macarulla, Teresa; Ramos, Francisco Javier; Dimitrijević, Saša; Zoellner, Ulrike; Tang, Pui; Stumm, Michael; Lane, Heidi A.; Lebwohl, David; Baselga, J.

doi:10.1200/jco.2007.14.5482

Cited by 501 publications

(397 citation statements)

References 46 publications

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“…Both everolimus and LY294002 acted mainly by induction of cell-cycle arrest, particularly in G 1 phase, which was similar with other study using PI3K and mTOR dual inhibitors (17). Target mTOR therapy alone can cause a multiple feedback loops and cross-talk with other signaling pathways, which may lead to pAkt activation and attenuate the responses to mTOR inhibition (14). Here, everolimus alone or combination with tamoxifen treatment can inhibit mTOR activity, but pAkt expression was upregulated in ER-positive breast cancer cell lines and in vivo tumor model, which may explain the relative low response rate in metastatic breast cancer therapy (11).…”

Section: Discussionsupporting

confidence: 71%

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Dual Inhibition of PI3K and mTOR Mitigates Compensatory AKT Activation and Improves Tamoxifen Response in Breast Cancer

Chen

Zhao

Hao

et al. 2013

Molecular Cancer Research

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Everolimus, an mTOR inhibitor, showed great clinical efficacy in combination with tamoxifen, letrozole, or exemestane for the treatment of estrogen receptor-positive (ER+) breast cancer. However, its antitumor activity was shown to be compromised by a compensatory process involving AKT activation. Here, it was determined whether combining an additional PI3K inhibitor can reverse this phenomenon and improve treatment efficacy. In breast cancer cells

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Section: Discussionsupporting

confidence: 71%

“…Baselga and colleagues showed that pAkt expression was upregulated in 50% of solid tumors treated with everolimus alone in a phase I study, which may attenuate the response with mTOR inhibitor (14). Among all the upstream signaling pathways in the mTOR complex, PI3K pathway is the most relevant in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Dual Inhibition of PI3K and mTOR Mitigates Compensatory AKT Activation and Improves Tamoxifen Response in Breast Cancer

Chen

Zhao

Hao

et al. 2013

Molecular Cancer Research

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“…1B). The differential response of these lines was consistently maintained across a range of everolimus concentrations, including the clinically relevant concentration of 50 n m (Tabernero et al ., 2008). No difference in everolimus response and the anatomical location along the biliary tract from which the cell lines originated was observed (Fig.…”

Section: Resultsmentioning

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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“…In both cases, rapamycin relieves feedback inhibition and promotes PI3K -AKT survival signaling. The clinical relevance of losing feedback inhibition is emphasized in human trials that find rapamycin increases AKT activation in many malignancies (O'Reilly et al 2006;Tabernero et al 2008;Sudarsanam and Johnson 2010). Rapamycin can also activate the MAPK pathway, providing another potential avenue to resistance (Carracedo et al 2008).…”

Section: Mtor and Cell Survivalmentioning

confidence: 99%

mTOR-Dependent Cell Survival Mechanisms

Hung

García-Haro

Sparks

et al. 2012

Cold Spring Harbor Perspectives in Biology

169

135

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The mechanistic target of rapamycin (mTOR) kinase is a conserved regulator of cell growth, proliferation, and survival. In cells, mTOR is the catalytic subunit of two complexes called mTORC1 and mTORC2, which have distinct upstream regulatory signals and downstream substrates. mTORC1 directly senses cellular nutrient availability while indirectly sensing circulating nutrients through growth factor signaling pathways. Cellular stresses that restrict growth also impinge on mTORC1 activity. mTORC2 is less well understood and appears only to sense growth factors. As an integrator of diverse growth regulatory signals, mTOR evolved to be a central signaling hub for controlling cellular metabolism and energy homoeostasis, and defects in mTOR signaling are important in the pathologies of cancer, diabetes, and aging. Here we discuss mechanisms by which each mTOR complex might regulate cell survival in response to metabolic and other stresses.

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Dose- and Schedule-Dependent Inhibition of the Mammalian Target of Rapamycin Pathway With Everolimus: A Phase I Tumor Pharmacodynamic Study in Patients With Advanced Solid Tumors

Abstract: Everolimus achieved mTOR signaling inhibition at doses below the DLT. A dosage of 10 mg/d or 50 mg/wk is recommended for further development.

Cited by 501 publications

References 46 publications

Dual Inhibition of PI3K and mTOR Mitigates Compensatory AKT Activation and Improves Tamoxifen Response in Breast Cancer

Dual Inhibition of PI3K and mTOR Mitigates Compensatory AKT Activation and Improves Tamoxifen Response in Breast Cancer

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

mTOR-Dependent Cell Survival Mechanisms

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