Figure 8. Model for AXL and EGFR cooperation in cetuximab resistance.

Cetuximab resistance is characterized by increased AXL mRNA and protein expression, EGFR activation, and MAPK pathway signaling. In Ctx^R cells, increased EGFR ligand (L) production leads to AXL and EGFR association and transactivation. This results in MAPK and c-Jun signaling and subsequent increases in AXL transcription. Increases in AXL mRNA result in elevated AXL protein levels and maintenance of EGFR activation and signaling. This positive feedback loop results in the constitutive activation of both AXL and EGFR in Ctx^R cells and thereby mediates cetuximab resistance.