The anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) cetuximab and panitumumab are effective in a subset of RAS/BRAF Wild-Type (WT) metastatic colorectal cancers (mCRCs). Despite RAS-driven selection, not all patients will respond to EGFR inhibitors and the onset of secondary resistance limits their clinical benefit.
We have tested, in vitro and in vivo, the effects of novel generation anti-EGFR inhibitors such as SYM004 in a panel of colorectal cancer (CRC) models with acquired resistance to cetuximab that we have generated in our laboratory. SYM004 is a 1:1 mixture of two recombinant human mouse chimeric mAbs directed against non-overlapping epitopes of the EGFR. The binding site of the two antibodies is different from cetuximab. A unique feature of SYM004 is its ability to mediate rapid EGFR internalization and subsequent degradation of internalized receptors via EGFR cross-linking.
SYM004 shows a potent anti-proliferative effect in cetuximab-resistant CRC cells. In particular we have already demonstrated that in cetuximab-resistant CRC cells, cell proliferation, and survival pathways are activated by MET. Interestingly overexpression of TGF-a, a specific EGFR ligand, induced formation of EGFR-MET hetero-dimers, with subsequent MET phosphorylation and activation. SYM004 induces reduction on MET phosphorylation in these cell lines. SYM004 treatment determined also a significant induction of apoptosis in cetuximab-resistant CRC cells and a strong anti-proliferative activity by inhibition of phospho-MAPK and phospho-AKT in these cell lines. Moreover, in others two model of cetuximab-resistant CRC cell with HER2 amplification or EGFR S492R mutation, SYM004 is able to overcome acquired resistance to cetuximab throw inhibition of proliferation and MAPK /AKT pathways activation. The antitumor activity has been confirmed by the in vivo xenografts CRC models.
These results suggest that the treatment with SYM004 could be a strategy for overcoming resistance to first generation of anti-EGFR therapies in CRC.
Clinical trial identification
Legal entity responsible for the study
Second University of Naples
All authors have declared no conflicts of interest.