کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10816010 | 1058535 | 2014 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
p70S6 kinase is a critical node that integrates HER-family and PI3 kinase signaling networks
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کلمات کلیدی
EGFRTissue Protein Extraction ReagentT-PERRPPAFOXHNSCCRTK4E-BP1eIF4EmTORPI3KpKap70S6KMAPK - MAPKp70S6 kinase - p70S6 کینازPI3 kinase - PI3 کینازreverse phase protein array - آرایه پروتئین معکوسforkhead box - جعبه جعبهNSCLC - سرطان ریوی غیر سلول کوچکNon-small cell lung cancer - سرطان غیر سلول کوچک ریهSignaling networks - شبکه های سیگنالینگeukaryotic initiation factor 4E - عامل آغاز کننده یوکاریوتی 4Ephosphoinositide-3-kinase - فسفونیوییدید-3-کینازmammalian target of rapamycin - هدف پستانداران رپامایسینAdaptive response - پاسخ سازگارprotein kinase A - پروتئین کیناز Amitogen activated protein kinase - پروتئین کیناز فعال Mitogen فعال استHead and neck squamous cell carcinoma - کارسینوم سلول سنگفرشی سر و گردنMAP kinase - کیناز MAPReceptor Tyrosine Kinase - گیرنده تیروزین کینازEpidermal growth factor receptor - گیرنده فاکتور رشد اپیدرمال
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: p70S6 kinase is a critical node that integrates HER-family and PI3 kinase signaling networks p70S6 kinase is a critical node that integrates HER-family and PI3 kinase signaling networks](/preview/png/10816010.png)
چکیده انگلیسی
Therapies targeting oncogenic drivers rapidly induce compensatory adaptive responses that blunt drug effectiveness, contributing to therapeutic resistance. Adaptive responses are characteristic of robust cell signaling networks, and thus there is increasing interest in drug combinations that co-target the driver and the adaptive response. An alternative approach to co-inhibiting oncogenic and adaptive targets is to identify a critical node where the activities of these targets converge. Nodes of convergence between signaling modules represent potential therapeutic vulnerabilities because their inhibition could result in the collapse of the network, leading to enhanced cytotoxicity. In this report we demonstrate that p70S6 kinase (p70S6K) can function as a critical node linking HER-family and phosphoinositide-3-kinase (PI3K) pathway signaling. We used high-throughput combinatorial drug screening to identify adaptive survival responses to targeted therapies, and found that HER-family and PI3K represented compensatory signaling pathways. Co-targeting these pathways with drug combinations caused synergistic cytotoxicity in cases where inhibition of neither target was effective as a monotherapy. We utilized Reverse Phase Protein Arrays and determined that phosphorylation of ribosomal protein S6 was synergistically down-regulated upon HER-family and PI3K/mammalian target of rapamycin (mTOR) co-inhibition. Expression of constitutively active p70S6K protected against apoptosis induced by combined HER-family and PI3K/mTOR inhibition. Direct inhibition of p70S6K with small molecule inhibitors phenocopied HER-family and PI3K/mTOR co-inhibition. These data implicate p70S6K as a critical node in the HER-family/PI3K signaling network. The ability of direct inhibitors of p70S6K to phenocopy co-inhibition of two upstream signaling targets indicates that identification and targeting of critical nodes can overcome adaptive resistance to targeted therapies.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cellular Signalling - Volume 26, Issue 8, August 2014, Pages 1627-1635
Journal: Cellular Signalling - Volume 26, Issue 8, August 2014, Pages 1627-1635
نویسندگان
Mark J. Axelrod, Vicki Gordon, Rolando E. Mendez, Stephanie S. Leimgruber, Mark R. Conaway, Elizabeth R. Sharlow, Mark J. Jameson, Daniel G. Gioeli, Michael J. Weber,