Clinically Viable Gene Expression Assays with Potential for Predicting Benefit from MEK Inhibitors

被引:21
作者
Brant, Roz [1 ]
Sharpe, Alan [2 ]
Liptrot, Tom [3 ]
Dry, Jonathan R. [4 ]
Harrington, Elizabeth A. [2 ]
Barrett, J. Carl [5 ]
Whalley, Nicky [6 ]
Womack, Christopher [7 ]
Smith, Paul [6 ]
Hodgson, Darren R. [1 ]
机构
[1] AstraZeneca, Translat Sci, Oncol iMED, Macclesfield, Cheshire, England
[2] AstraZeneca, Oncol iMED, Cambridge, England
[3] Christie NHS Fdn Trust, Informat, Manchester, Lancs, England
[4] AstraZeneca, Oncol iMED, iSci, Waltham, MA USA
[5] AstraZeneca, Oncol iMED, Translat Sci, Waltham, MA USA
[6] AstraZeneca, Canc Biosci, Cambridge, England
[7] Histologix Ltd, Nottingham, England
关键词
CELL LUNG-CANCER; PATHWAY SIGNATURES; KRAS MUTATION; DEPENDENCE; EGFR;
D O I
10.1158/1078-0432.CCR-16-0021
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 NSCLC in silico. NanoString 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 with KRAS siRNA and MEK inhibitor, were investigated in cell lines. Second, the association of the signatures with KRAS mutation 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 signatures in vitro. Technical and biological repli-cates 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 and KRAS mutation in 50 NSCLC samples. The signatures identify overlapping but distinct candidate patient populations from each other and from KRAS mutation 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 with KRAS mutation testing. The predictive power of the MEK signature should be studied further in clinical trials. (C) 2016 AACR.
引用
收藏
页码:1471 / 1480
页数:10
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