title: Clinically Viable Gene Expression Assays with Potential for Predicting Benefit from MEK Inhibitors.
abstract: Purpose:To develop a clinically viable gene expression assay to measure RAS/RAF/MEK/ERK (RAS-ERK) pathway output suitable for hypothesis testing in non-small cell lung cancer (NSCLC) clinical studies.Experimental Design:A published MEK functional activation signature (MEK signature) that measures RAS-ERK functional output was optimized for NSCLCin silicoNanoString assays were developed for the NSCLC optimized MEK signature and the 147-gene RAS signature. First, platform transfer from Affymetrix to NanoString, and signature modulation following treatment withKRASsiRNA and MEK inhibitor, were investigated in cell lines. Second, the association of the signatures withKRASmutation status, dynamic range, technical reproducibility, and spatial and temporal variation was investigated in NSCLC formalin-fixed paraffin-embedded tissue (FFPET) samples.Results:We observed a strong cross-platform correlation and modulation of signaturesin vitroTechnical and biological replicates showed consistent signature scores that were robust to variation in input total RNA; conservation of scores between primary and metastatic tumor was statistically significant. There were statistically significant associations between high MEK (P= 0.028) and RAS (P= 0.003) signature scores andKRASmutation in 50 NSCLC samples. The signatures identify overlapping but distinct candidate patient populations from each other and fromKRASmutation testing.Conclusions:We developed a technically and biologically robust NanoString gene expression assay of MEK pathway output, compatible with the quantities of FFPET routinely available. The gene signatures identified a different patient population for MEK inhibitor treatment compared withKRASmutation testing. The predictive power of the MEK signature should be studied further in clinical trials.Clin Cancer Res; 23(6); 1471-80. ©2016 AACRSee related commentary by Xue and Lito, p. 1365.
authors.affiliation: Translational Science, Oncology iMED, AstraZeneca, Macclesfield, UK.
authors.forename: Roz
authors.initials: R
authors.lastname: Brant
authors.affiliation: Oncology iMED, AstraZeneca, Cambridge, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Sharpe
authors.affiliation: Informatics, The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Liptrot
authors.affiliation: iScience, Oncology iMED, AstraZeneca, Waltham, Massachusetts.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Dry
authors.affiliation: Oncology iMED, AstraZeneca, Cambridge, UK.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Harrington
authors.affiliation: Translational Science, Oncology iMED, AstraZeneca, Waltham, Massachusetts.
authors.forename: J Carl
authors.initials: JC
authors.lastname: Barrett
authors.affiliation: Cancer Biosciences, AstraZeneca, Cambridge, UK.
authors.forename: Nicky
authors.initials: N
authors.lastname: Whalley
authors.affiliation: Histologix Ltd, Nottingham, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Womack
authors.affiliation: Cancer Biosciences, AstraZeneca, Cambridge, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Smith
authors.affiliation: Translational Science, Oncology iMED, AstraZeneca, Macclesfield, UK. Darren.Hodgson@astrazeneca.com.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Hodgson
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D003198:Computer Simulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D034741:RNA, Small Interfering; D059467:Transcriptome / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)