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Journal articles
Protein biomarkers predictive for response to anti-EGFR treatment in RAS wild-type metastatic colorectal carcinoma
Abstract : 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.
Keywords :
Fluorouracil
Genes
ras
Humans
Leucovorin
Male
MAP Kinase Signaling System
Middle Aged
Mutation
Organoplatinum Compounds
Monoclonal
Antibodies
Wnt Signaling Pathway
Retrospective Studies
ErbB-2
ErbB-3
Response Evaluation Criteria in Solid Tumors
Receptor
Epidermal Growth Factor
Female
Protein Kinase Inhibitors
Proto-Oncogene Proteins B-raf
Phosphorylation
Antineoplastic Combined Chemotherapy Protocols
Biomarkers
Tumor
Camptothecin
Carcinoma
Cetuximab
Class I Phosphatidylinositol 3-Kinases
Colorectal Neoplasms
Drug Resistance
Neoplasm
Epigenesis
Genetic
Cited literature [44 references]
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01682154
Contributor : Laurent Jonchère Connect in order to contact the contributor
Submitted on : Wednesday, January 17, 2018 - 3:33:24 PM
Last modification on : Wednesday, November 23, 2022 - 12:02:09 PM
Contributor : Laurent Jonchère Connect in order to contact the contributor
Submitted on : Wednesday, January 17, 2018 - 3:33:24 PM
Last modification on : Wednesday, November 23, 2022 - 12:02:09 PM