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.
Highlights
EGFR-targeting monoclonal antibodies, such as cetuximab (Erbitux®) [1, 2], are important standard of care (SOC) targeted therapies for treating metastatic colorectal carcinoma, excluding those with KRAS mutations at codons 12 and 13, and offer clinical benefit for a subset of mCRC patients [3]
A recent retrospective analysis of multiple phase-III trials unexpectedly concluded that patients with KRAS codon 13 mutation (G13D) seem to benefit from the treatment [6], and our recent observation on a mouse clinical trial (MCT) using a cohort of randomly selected CRC patient-derived xenografts (PDXs) clearly supported the same conclusion [7, 8]
We have explored predictive biomarkers for CRCcetuximab response using MCT datasets, those based on genetic alterations [7], and those based on gene expression
Summary
EGFR-targeting monoclonal antibodies, such as cetuximab (Erbitux®) [1, 2], are important standard of care (SOC) targeted therapies for treating metastatic colorectal carcinoma (mCRC), excluding those with KRAS mutations at codons 12 and 13, and offer clinical benefit for a subset of mCRC patients [3]. Only 35~50% of wild-type KRAS CRC patients responded to cetuximab [2, 4] and only ~10% of mCRC patients respond to cetuximab monotherapy as a second line treatment [5]. Caution has been advised on the use of cetuximab in some KRAS-12/13 wild type patients
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