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.
Guo, S., Chen, D., Huang, X., Cai, J., Wery, J.-P., & Li, Q.-X. (2016). Cetuximab response in CRC patient-derived xenografts seems predicted by an expression based RAS pathway signature. Oncotarget, 7(31). https://doi.org/10.18632/oncotarget.10499