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Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244)
Authors
Alexander Graham
Andrew Cassidy
+30 more
Baldassarre
Barry S. Taylor
Brose
Carolyn Haggerty
Chris Harbron
Christine A. Pratilas
Christine Chresta
Darren Hodgson
David B. Solit
Feng Xing
Garry Beran
Gillian Ellison
Helen Brown
Jonathan R. Dry
Judy Dering
Leisl Packer
Mark Cockerill
Mitchell Stark
Natalie Byrne
Neal Rosen
Nicholas K. Hayward
O'Hagan
Paul D. Smith
Richard S. Finn
Rose McCormack
Sandra Pavey
Sarah Runswick
Sugandha Ravishankar
Tim French
Vanessa Bonazzi
Publication date
1 January 2010
Publisher
'American Association for Cancer Research (AACR)'
Doi
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on
PubMed
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
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