Fig. 8.

Schematic illustration of EGFR axis and MET/RON axis crosstalk in cetuximab resistance in CRC. Active EGFR and associated downstream signaling pathways confer several advantages to CRC cells including proliferation and/or evading apoptosis. Cetuximab counters EGFR signaling, but in cetuximab resistance, the shared downstream signaling pathways may be activated by other RTKs like MET/RON. MET/RON signaling may be inhibited at the receptor level by crizotinib, or at the ligand maturation level by exogenous inhibition of HGF/HGFL proteases HGFA, Hepsin, and Matriptase, or by endogenous protease inhibitors, PCI, HAI-I, and HAI-II. Inhibition of HGF/HGFL maturation may thus be a new strategy to combine with cetuximab inhibition in CRC