title: Cetuximab response in CRC patient-derived xenografts seems predicted by an expression based RAS pathway signature.
abstract: 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.
authors.affiliation: Division of Translational Oncology, Crown Bioscience, Inc., Santa Clara, CA 95054, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Guo
authors.affiliation: Division of Translational Oncology, Crown Bioscience, Inc., Santa Clara, CA 95054, USA.
authors.forename: Dawei
authors.initials: D
authors.lastname: Chen
authors.affiliation: Division of Translational Oncology, Crown Bioscience, Inc., Santa Clara, CA 95054, USA.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Huang
authors.affiliation: Division of Translational Oncology, Crown Bioscience, Inc., Santa Clara, CA 95054, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Cai
authors.affiliation: Division of Translational Oncology, Crown Bioscience, Inc., Santa Clara, CA 95054, USA.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Wery
authors.affiliation: Division of Translational Oncology, Crown Bioscience, Inc., Santa Clara, CA 95054, USA.|State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China.
authors.forename: Qi-Xiang
authors.initials: QX
authors.lastname: Li
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D000068818:Cetuximab / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D008024:Ligands; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D018631:ras Proteins; D000068818:Cetuximab
keywords: Erbitux; PDX; biomarker; expression signature; patient stratification