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.
authors.affiliation: Cancer Bioscience, DECS, and Clinical Biomarker Group, AstraZeneca R&D, Alderley Park, Macclesfield, United Kingdom. Jonathan.Dry@astrazeneca.com
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Dry
authors.forename: Sandra
authors.initials: S
authors.lastname: Pavey
authors.forename: Christine A
authors.initials: CA
authors.lastname: Pratilas
authors.forename: Chris
authors.initials: C
authors.lastname: Harbron
authors.forename: Sarah
authors.initials: S
authors.lastname: Runswick
authors.forename: Darren
authors.initials: D
authors.lastname: Hodgson
authors.forename: Christine
authors.initials: C
authors.lastname: Chresta
authors.forename: Rose
authors.initials: R
authors.lastname: McCormack
authors.forename: Natalie
authors.initials: N
authors.lastname: Byrne
authors.forename: Mark
authors.initials: M
authors.lastname: Cockerill
authors.forename: Alexander
authors.initials: A
authors.lastname: Graham
authors.forename: Garry
authors.initials: G
authors.lastname: Beran
authors.forename: Andrew
authors.initials: A
authors.lastname: Cassidy
authors.forename: Carolyn
authors.initials: C
authors.lastname: Haggerty
authors.forename: Helen
authors.initials: H
authors.lastname: Brown
authors.forename: Gillian
authors.initials: G
authors.lastname: Ellison
authors.forename: Judy
authors.initials: J
authors.lastname: Dering
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.forename: Mitchell
authors.initials: M
authors.lastname: Stark
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bonazzi
authors.forename: Sugandha
authors.initials: S
authors.lastname: Ravishankar
authors.forename: Leisl
authors.initials: L
authors.lastname: Packer
authors.forename: Feng
authors.initials: F
authors.lastname: Xing
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finn
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
authors.forename: Tim
authors.initials: T
authors.lastname: French
authors.forename: Paul D
authors.initials: PD
authors.lastname: Smith
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000096:biosynthesis / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D019869:Phosphatidylinositol 3-Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D020930:MAP Kinase Kinase Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human