期刊
BRITISH JOURNAL OF CANCER
卷 117, 期 12, 页码 1819-1827出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2017.353
关键词
colorectal cancer; resistance; EGFR; biomarkers; cell signalling; RPPA; PI3K
类别
资金
- Institut Curie Evaluation Committee of Translational Research (CEST)
- Institut Carnot Curie-Cancer
Background: Metastatic colorectal cancer (mCRC) patients with mutant KRAS or NRAS are ineligible for anti-epidermal growth factor receptor (anti-EGFR) therapy, as RAS mutations activate downstream pathways independently of EGFR and induce primary resistance. However, even among RAS wild-type (WT) patients, only a fraction responds to anti-EGFR therapy, suggesting that other mechanisms of resistance exist. We hypothesise that different (epi) genetic alterations can lead to primary anti-EGFR resistance and that the crucial end point is the activation of protein signalling pathways. Methods: We analysed the expression and activation of proteins involved in cell signalling, using reverse phase protein arrays, on a multicentre French cohort of RAS WT mCRC treated with anti-EGFR treatment. Results: We identify activated EGFR and HER3 as protein biomarkers predictive for better overall survival. Active EGFR signalling and downstream PI3K, but not MAPK, pathway activation are associated with response to anti-EGFR treatment. Left-sided mCRC displays active ErbB2/3 and Wnt pathways and a better response to anti-EGFR therapy compared to right-sided mCRC. Conclusions: We identify active EGFR and PI3K signalling as a key factor for response to anti-EGFR treatment in mCRC and highlight the importance of developing these biomarkers in clinical practice for the selection of RAS WT mCRC patients that would benefit from anti-EGFR treatment.
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