Cetuximab is an approved treatment for metastatic colorectal carcinoma (mCRC) with codon 12/13-KRAS mutations, recently questioned for its validity, and alternative mutation-based biomarkers were proposed. We set out to investigate whether an expression signature can also predict response by utilizing a cetuximab mouse clinical trial (MCT) dataset on a cohort of 25 randomly selected EGFR+ CRC patient-derived xenografts (PDXs). While we found that the expression of EGFR and its ligands are not predictive of the cetuximab response, we tested a published RAS pathway signature, a 147-gene expression signature proposed to describe RAS pathway activity, against this MCT dataset. Interestingly, our study showed that the observed cetuximab activity has a strong correlation with the RAS pathway signature score, which was also demonstrated to have a certain degree of correlation with a historic clinical dataset. Altogether, the independent validations in unrelated datasets from independent cohort of CRCs strongly suggest that RAS pathway signature may be a relevant expression signature predictive of CRC response to cetuximab. Our data seem to suggest that an mRNA expressing signature may also be developed as a predictive biomarker for drug response, similarly to genetic mutations.