Beyond the well recognized effect of KRAS mutations in determining de novo ineffi cacy of cetuximab in metastatic colorectal cancer, there is a need for a biomarker signature for predicting cetuximab effi cacy in KRAS wild-type tumors. In this paper by Oliveras-Ferraros et al, cetuximab-adapted EGFR gene-amplifi ed KRAS WT tumor cell populations were induced by stepwise chronic exposure of A431 epidermoid cancer cells to cetuximab. Genome-wide analyses of 44 K Agilent's whole human arrays were bioinformatically evaluated by GSEA-based screening of the KEGG pathway database. Molecular functioning of cetuximab was found to depend on: 1.) the occurrence of a positive feedback loop on EGFR activation driven by genes coding for EGFR ligands; 2.) the lack of a negative feedback on MAPK activation regulated by dualspecifi city phosphatases, and; 3.) the transcriptional status of gene pathways controlling the Epithelial-to-Mesenchymal Transition (EMT) and its reversal (MET) program. Quantitative RTPCR, high-content immunostaining and fl ow-cytometry analyses confi rmed that cetuximab effi cacy depends on its ability to promote: a) stronger cell-cell contacts by up-regulating the expression of the epithelial markers E-cadherin and occludin; b) down-regulation of the epithelial transcriptional repressors Zeb, Snail and Slug accompanied by restoration of cortical F-actin; and c) complete prevention of the CD44pos/CD24neg/low mesenchymal immunophenotype. The impact of EGFR ligands/MAPK phosphatases gene transcripts in predicting cetuximab effi cacy in KRAS WT tumors may be tightly linked with the ability of cetuximab to concurrently reverse the EMT status, a pivotal property of migrating cancer stem cells.