mTOR inhibition, a potential novel approach for bronchial carcinoids

Dong, Mei; Yao, James C.

doi:10.1530/erc-10-0290

Cited by 18 publications

(10 citation statements)

References 22 publications

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“…However, ACCs in the poor prognosis group displayed more advanced disease, subsequently confounding the issue of whether these subgroups correspond to distinct stages of the same disease or to distinct ACC types. Statistical independence of transcriptome-based prognostic information from stage seems to argue in favor of the latter [26]. …”

Section: Part I Histogenesis Of Conventional Adrenocortical Carcinomasmentioning

confidence: 99%

Adrenocortical neoplasia: evolving concepts in tumorigenesis with an emphasis on adrenal cortical carcinoma variants

Krijger

Papathomas

2011

Virchows Arch

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Adrenocortical carcinoma (ACC) is a rare, heterogeneous malignancy with a poor prognosis. According to WHO classification 2004, ACC variants include oncocytic ACCs, myxoid ACCs and ACCs with sarcomatous areas. Herein, we provide a comprehensive review of these rare subtypes of adrenocortical malignancy and emphasize their clinicopathological features with the aim of elucidating aspects of diagnostic categorization, differential diagnostics and biological behavior. The issue of current terminology, applied to biphasic tumors with pleomorphic, sarcomatous or sarcomatoid elements arising in adrenal cortex, is also discussed. We additionally present emerging evidence concerning the adrenal cortical tumorigenesis and the putative adenoma–carcinoma sequence as well.

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Section: Part I Histogenesis Of Conventional Adrenocortical Carcinomasmentioning

confidence: 99%

Adrenocortical neoplasia: evolving concepts in tumorigenesis with an emphasis on adrenal cortical carcinoma variants

Krijger

Papathomas

2011

Virchows Arch

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“…Furthermore, the majority of these genes are located in the PI3K/AKT/mTOR pathway. The mTOR inhibitors were reportedly effective in selected patients with TC/AC (21,22); however, the mechanism is unclear. Therefore, the present study aimed to examine the expression of mTOR and mutations in the PI3K/AKT/mTOR pathway genes in patients with TC/AC.…”

Section: Introductionmentioning

confidence: 99%

PI3K/AKT/mTOR pathway in pulmonary carcinoid tumours

Zhang

Wang

2017

Oncology Letters

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The present study examined the expression of mammalian target of rapamycin (mTOR) and mutations in the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway in 54 patients with typical carcinoid tumours (TC) or atypical carcinoid tumours (AC). In total, 54 bronchopulmonary neuroendocrine tumour (NET) surgical specimens, consisting of 17 TC, 8 AC, 17 large-cell neuroendocrine carcinoma (LCNEC), and 12 small-cell lung carcinoma (SCLC) samples, were tested for mTOR by immunohistochemistry, and 104 exon sites were tested in the PI3K/AKT/mTOR pathway by nested polymerase chain reaction. It was found that the positive rates for mTOR expression in TC/AC and LCNEC/SCLC were 60 (15/25) and 55.2% (16/29), respectively. In total, 4 missense mutations were found in 3 patients with TC/AC, including mutations in exon 48 of mTOR (c.6667C>T), exon 21 of tuberous sclerosis complex (TSC) 1 (c.2765G>A), and exons 12 (c.1265C>T) and 19 (c.2148C>T) of TSC2. To the best of our knowledge, mutations in exon 48 of mTOR and exon 21 of TSC1 have not been previously reported. Tissues from patients with single mutations exhibited strong positive mTOR immunohistochemical staining, and tissues from patients with double mutations were weakly positive. The same mutations were not observed in SCLC or LCNEC. In conclusion, gene mutations were observed and an association between the gene mutations and mTOR expression were indicated in the PI3K/AKT/mTOR pathway in TC/AC tumours. Those mutations may be driver genes and treatment targets.

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“…mTOR associates with two sets of different proteins, forming either the mTORC1 complex or the mTORC2 complex, with the former being more sensitive to rapamycin than the latter (Loewith et al 2002). It has been demonstrated that the mTOR pathway is constitutively activated in NETs , providing the basis for the development of specific mTOR inhibitors as new therapeutic tools for NETs (Dong et al 2012), including BCs (Dong & Yao 2011). Despite their potential efficacy as anticancer agents, mTOR inhibitors have demonstrated erratic clinical activity (Wang & Sun 2009), indicating the need to identify possible efficacy markers.…”

Section: Introductionmentioning

confidence: 99%

mTOR, p70S6K, AKT, and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids

Gagliano¹,

Bellio²,

Gentilin³

et al. 2013

Endocrine-Related Cancer

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Bronchial carcinoids (BCs) are rare neuroendocrine tumors that are still orphans of medical treatment. Human BC primary cultures may display resistance to everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), in terms of cell viability reduction. Our aim was to assess whether the novel dual phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor NVP-BEZ235 is effective in everolimus-resistant human BC tissues and cell lines. In addition, we searched for possible markers of the efficacy of mTOR inhibitors that may help in identifying the patients who may benefit from treatment with mTOR inhibitors, sparing them from ineffective therapy. We found that NVP-BEZ235 is twice as potent as everolimus in reducing cell viability and activating apoptosis in human BC tissues that display sensitivity to mTOR inhibitors, but is not effective in everolimus-resistant BC tissues and cell lines that bypass cyclin D1 downregulation and escape G0/G1 blockade. Rebound AKT activation was not observed in response to treatment with either mTOR inhibitor in the 'resistant' BC cells. In addition to total mTOR levels, putative markers of the sensitivity of BCs to mTOR inhibitors are represented by AKT, p70S6K (RPS6KB2), and ERK1/2 (MAPK3/1) protein levels. Finally, we validated these markers in an independent BC group. These data indicate that the dual PI3K/mTOR inhibitor NVP-BEZ235 is more potent than everolimus in reducing the proliferation of human BC cells. 'Resistant' cells display lower levels of mTOR, p70S6K, AKT, and ERK1/2, indicating that these proteins may be useful as predictive markers of resistance to mTOR and PI3K/mTOR inhibitors in human BCs.

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mTOR inhibition, a potential novel approach for bronchial carcinoids

Cited by 18 publications

References 22 publications

Adrenocortical neoplasia: evolving concepts in tumorigenesis with an emphasis on adrenal cortical carcinoma variants

Adrenocortical neoplasia: evolving concepts in tumorigenesis with an emphasis on adrenal cortical carcinoma variants

PI3K/AKT/mTOR pathway in pulmonary carcinoid tumours

mTOR, p70S6K, AKT, and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids

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