FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2138832277> ?p ?o ?g. }

• W2138832277 abstract "Upregulation of PI3K/Akt/mTOR signalling in endocrine-resistant breast cancer (BC) has identified mTOR as an attractive target alongside anti-hormones to control resistance. RAD001 (everolimus/Afinitor®), an allosteric mTOR inhibitor, is proving valuable in this setting; however, some patients are inherently refractory or relapse during treatment requiring alternative strategies. Here we evaluate the potential for novel dual mTORC1/2 mTOR kinase inhibitors, exemplified by AZD8055, by comparison with RAD001 in ER + endocrine resistant BC cells. In vitro models of tamoxifen (TamR) or oestrogen deprivation resistance (MCF7-X) were treated with RAD001 or AZD8055 alone or combined with anti-hormone fulvestrant. Endpoints included growth, cell proliferation (Ki67), viability and migration, with PI3K/AKT/mTOR signalling impact monitored by Western blotting. Potential ER cross-talk was investigated by immunocytochemistry and RT-PCR. RAD001 was a poor growth inhibitor of MCF7-derived TamR and MCF7-X cells (IC50 ≥1 μM), rapidly inhibiting mTORC1 but not mTORC2/AKT signalling. In contrast AZD8055, which rapidly inhibited both mTORC1 and mTORC2/AKT activity, was a highly effective (P <0.001) growth inhibitor of TamR (IC50 18 nM) and MCF7-X (IC50 24 nM), and of a further T47D-derived tamoxifen resistant model T47D-tamR (IC50 19 nM). AZD8055 significantly (P <0.05) inhibited resistant cell proliferation, increased cell death and reduced migration. Furthermore, dual treatment of TamR or MCF7-X cells with AZD8055 plus fulvestrant provided superior control of resistant growth versus either agent alone (P <0.05). Co-treating with AZD8055 alongside tamoxifen (P <0.01) or oestrogen deprivation (P <0.05) also effectively inhibited endocrine responsive MCF-7 cells. Although AZD8055 inhibited oestrogen receptor (ER) ser167 phosphorylation in TamR and MCF7-X, it had no effect on ER ser118 activity or expression of several ER-regulated genes, suggesting the mTOR kinase inhibitor impact was largely ER-independent. The capacity of AZD8055 for ER-independent activity was further evidenced by growth inhibition (IC5018 and 20 nM) of two acquired fulvestrant resistant models lacking ER. This is the first report demonstrating dual mTORC1/2 mTOR kinase inhibitors have potential to control acquired endocrine resistant BC, even under conditions where everolimus fails. Such inhibitors may prove of particular benefit when used alongside anti-hormonal treatment as second-line therapy in endocrine resistant disease, and also potentially alongside anti-hormones during the earlier endocrine responsive phase to hinder development of resistance." @default.
• W2138832277 created "2016-06-24" @default.
• W2138832277 creator A5012364827 @default.
• W2138832277 creator A5015790021 @default.
• W2138832277 creator A5029873345 @default.
• W2138832277 creator A5029966106 @default.
• W2138832277 creator A5040373927 @default.
• W2138832277 creator A5045893913 @default.
• W2138832277 creator A5054581463 @default.
• W2138832277 creator A5059111236 @default.
• W2138832277 date "2014-01-23" @default.
• W2138832277 modified "2023-10-09" @default.
• W2138832277 title "Impact of dual mTORC1/2 mTOR kinase inhibitor AZD8055 on acquired endocrine resistance in breast cancer in vitro" @default.
• W2138832277 cites W1965626427 @default.
• W2138832277 cites W1983621028 @default.
• W2138832277 cites W1983698019 @default.
• W2138832277 cites W1984849512 @default.
• W2138832277 cites W1985063806 @default.
• W2138832277 cites W1994186909 @default.
• W2138832277 cites W1995340851 @default.
• W2138832277 cites W2000493107 @default.
• W2138832277 cites W2004946118 @default.
• W2138832277 cites W2007110714 @default.
• W2138832277 cites W2013003434 @default.
• W2138832277 cites W2017605860 @default.
• W2138832277 cites W2025005089 @default.
• W2138832277 cites W2025887278 @default.
• W2138832277 cites W2026493214 @default.
• W2138832277 cites W2029348880 @default.
• W2138832277 cites W2035521247 @default.
• W2138832277 cites W2046410395 @default.
• W2138832277 cites W2048543876 @default.
• W2138832277 cites W2049761405 @default.
• W2138832277 cites W2055359615 @default.
• W2138832277 cites W2071877453 @default.
• W2138832277 cites W2073090360 @default.
• W2138832277 cites W2075511135 @default.
• W2138832277 cites W2080127092 @default.
• W2138832277 cites W2087547195 @default.
• W2138832277 cites W2089413248 @default.
• W2138832277 cites W2089668045 @default.
• W2138832277 cites W2089738145 @default.
• W2138832277 cites W2092419949 @default.
• W2138832277 cites W2095783009 @default.
• W2138832277 cites W2098629317 @default.
• W2138832277 cites W2100506877 @default.
• W2138832277 cites W2102148658 @default.
• W2138832277 cites W2105095453 @default.
• W2138832277 cites W2110059026 @default.
• W2138832277 cites W2112001957 @default.
• W2138832277 cites W2112893608 @default.
• W2138832277 cites W2112986537 @default.
• W2138832277 cites W2113365503 @default.
• W2138832277 cites W2113458582 @default.
• W2138832277 cites W2116622644 @default.
• W2138832277 cites W2117357260 @default.
• W2138832277 cites W2124792927 @default.
• W2138832277 cites W2125501362 @default.
• W2138832277 cites W2126783165 @default.
• W2138832277 cites W2132950000 @default.
• W2138832277 cites W2135501389 @default.
• W2138832277 cites W2143112776 @default.
• W2138832277 cites W2143439281 @default.
• W2138832277 cites W2146040288 @default.
• W2138832277 cites W2146778486 @default.
• W2138832277 cites W2147394591 @default.
• W2138832277 cites W2149218373 @default.
• W2138832277 cites W2151995827 @default.
• W2138832277 cites W2152289580 @default.
• W2138832277 cites W2154836325 @default.
• W2138832277 cites W2157995673 @default.
• W2138832277 cites W2159714906 @default.
• W2138832277 cites W2167188058 @default.
• W2138832277 cites W2167841373 @default.
• W2138832277 cites W2168006407 @default.
• W2138832277 cites W2168485476 @default.
• W2138832277 cites W2169689529 @default.
• W2138832277 cites W2312553905 @default.
• W2138832277 cites W4251622665 @default.
• W2138832277 doi "https://doi.org/10.1186/bcr3604" @default.
• W2138832277 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3978713" @default.
• W2138832277 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/24457069" @default.
• W2138832277 hasPublicationYear "2014" @default.
• W2138832277 type Work @default.
• W2138832277 sameAs 2138832277 @default.
• W2138832277 citedByCount "56" @default.
• W2138832277 countsByYear W21388322772014 @default.
• W2138832277 countsByYear W21388322772015 @default.
• W2138832277 countsByYear W21388322772016 @default.
• W2138832277 countsByYear W21388322772017 @default.
• W2138832277 countsByYear W21388322772018 @default.
• W2138832277 countsByYear W21388322772019 @default.
• W2138832277 countsByYear W21388322772020 @default.
• W2138832277 countsByYear W21388322772021 @default.
• W2138832277 countsByYear W21388322772022 @default.
• W2138832277 countsByYear W21388322772023 @default.
• W2138832277 crossrefType "journal-article" @default.
• W2138832277 hasAuthorship W2138832277A5012364827 @default.
• W2138832277 hasAuthorship W2138832277A5015790021 @default.
• W2138832277 hasAuthorship W2138832277A5029873345 @default.

• next