دورية أكاديمية
Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244)
| العنوان: | Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244) |
|---|---|
| المؤلفون: | Dry, Jonathan, Pavey, Sandra, Pratilas, Christine, Harbron, Chris, Runswick, Sarah, Hodgson, Darren, Chresta, Christine, McCormack, Rose, Byrne, Natalie, Cockerill, Mark, Graham, Alexander, Beran, Garry, Cassidy, Andrew, Haggerty, Carolyn, Brown, Helen, Ellison, Gillian, Dering, Judy, Taylor, Barry, Stark, Mitchell, Bonazzi, Vanessa, Ravishankar, Sugandha, Packer, Leisl, Xing, Feng, Solit, David, Finn, Richard, Rosen, Neal, Hayward, Nicholas, French, Tim, Smith, Paul |
| المصدر: | Cancer Research |
| بيانات النشر: | American Association for Cancer Research Inc. |
| سنة النشر: | 2010 |
| المجموعة: | Queensland University of Technology: QUT ePrints |
| مصطلحات موضوعية: | 5 (4 bromo 2 chloroanilino) 4 fluoro 1 methyl 1h benzimidazole 6 carbohydroxamic acid 2 hydroxyethyl ester, article, breast tumor, cancer model, colon, enzyme inhibitor, messenger RNA, mitogen activated protein kinase kinase, phosphatidylinositol 3 kinase |
| الوصف: | Selumetinib (AZD6244, ARRY-142886) is a selective, non-ATP-competitive inhibitor of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-1/2. The range of antitumor activity seen preclinically and in patients highlights the importance of identifying determinants of response to this drug. In large tumor cell panels of diverse lineage, we show that MEK inhibitor response does not have an absolute correlation with mutational or phospho-protein markers of BRAF/MEK, RAS, or phosphoinositide 3-kinase (PI3K) activity. We aimed to enhance predictivity by measuring pathway output through coregulated gene networks displaying differential mRNA expression exclusive to resistant cell subsets and correlated to mutational or dynamic pathway activity. We discovered an 18-gene signature enabling measurement of MEK functional output independent of tumor genotype. Where the MEK pathway is activated but the cells remain resistant to selumetinib, we identified a 13-gene signature that implicates the existence of compensatory signaling from RAS effectors other than PI3K. The ability of these signatures to stratify samples according to functional activation of MEK and/or selumetinib sensitivity was shown in multiple independent melanoma, colon, breast, and lung tumor cell lines and in xenograft models. Furthermore, we were able to measure these signatures in fixed archival melanoma tumor samples using a single RT-qPCR-based test and found intergene correlations and associations with genetic markers of pathway activity to be preserved. These signatures offer useful tools for the study of MEK biology and clinical application of MEK inhibitors, and the novel approaches taken may benefit other targeted therapies. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| العلاقة: | Dry, Jonathan, Pavey, Sandra, Pratilas, Christine, Harbron, Chris, Runswick, Sarah, Hodgson, Darren, Chresta, Christine, McCormack, Rose, Byrne, Natalie, Cockerill, Mark, Graham, Alexander, Beran, Garry, Cassidy, Andrew, Haggerty, Carolyn, Brown, Helen, Ellison, Gillian, Dering, Judy, Taylor, Barry, Stark, Mitchell, Bonazzi, Vanessa, Ravishankar, Sugandha, Packer, Leisl, Xing, Feng, Solit, David, Finn, Richard, Rosen, Neal, Hayward, Nicholas, French, Tim, & Smith, Paul (2010) Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244). Cancer Research, 70(6), pp. 2264-2273.; https://eprints.qut.edu.au/217943Test/; Faculty of Health; Institute of Health and Biomedical Innovation |
| الإتاحة: | https://doi.org/10.1158/0008-5472.CAN-09-1577Test https://eprints.qut.edu.au/217943Test/ |
| حقوق: | Consult author(s) regarding copyright matters ; This work is covered by copyright. Unless the document is being made available under a Creative Commons Licence, you must assume that re-use is limited to personal use and that permission from the copyright owner must be obtained for all other uses. If the document is available under a Creative Commons License (or other specified license) then refer to the Licence for details of permitted re-use. It is a condition of access that users recognise and abide by the legal requirements associated with these rights. If you believe that this work infringes copyright please provide details by email to qut.copyright@qut.edu.au |
| رقم الانضمام: | edsbas.A59DDF2 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |