Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244) Journal Article
| Authors: | Dry, J. R.; Pavey, S.; Pratilas, C. A.; Harbron, C.; Runswick, S.; Hodgson, D.; Chresta, C.; McCormack, R.; Byrne, N.; Cockerill, M.; Graham, A.; Beran, G.; Cassidy, A.; Haggerty, C.; Brown, H.; Ellison, G.; Dering, J.; Taylor, B. S.; Stark, M.; Bonazzi, V.; Ravishankar, S.; Packer, L.; Xing, F.; Solit, D. B.; Finn, R. S.; Rosen, N.; Hayward, N. K.; French, T.; Smith, P. D. |
| Article Title: | Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244) |
| Abstract: | 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. ©2010 AACR. |
| Keywords: | signal transduction; controlled study; human tissue; gene mutation; neoplasms; melanoma; reverse transcription polymerase chain reaction; gene expression; gene expression profiling; map kinase signaling system; genotype; genetic transcription; enzyme activation; enzyme inhibitor; cell line, tumor; phosphatidylinositol 3 kinase; cancer model; prediction; lung tumor; xenograft; messenger rna; reverse transcriptase polymerase chain reaction; quantitative analysis; colon tumor; breast tumor; drug response; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; pten phosphohydrolase; tumor cell; drug sensitivity; mitogen activated protein kinase kinase; 5 (4 bromo 2 chloroanilino) 4 fluoro 1 methyl 1h benzimidazole 6 carbohydroxamic acid 2 hydroxyethyl ester; genetic marker; benzimidazoles; proto-oncogene proteins b-raf; quantitative structure activity relation; map kinase kinase kinases |
| Journal Title: | Cancer Research |
| Volume: | 70 |
| Issue: | 6 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2010-03-15 |
| Start Page: | 2264 |
| End Page: | 2273 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-09-1577 |
| PUBMED: | 20215513 |
| PROVIDER: | scopus |
| PMCID: | PMC3166660 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 8" - "Export Date: 20 April 2011" - "CODEN: CNREA" - "Source: Scopus" |
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