SYM004, a novel generation anti-EGFR inhibitor, is able to overcome acquired resistance to cetuximab such as MET activation, ERBB2 amplification and EGFR mutations, in colorectal cancer models

Background

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.

Methods

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.

Results

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.

Conclusions

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

NA

Legal entity responsible for the study

Second University of Naples

Funding

Symphogen

Disclosure

All authors have declared no conflicts of interest.