Fig. 2.

Extrinsic mechanisms of resistance to anti-EGFR mAbs in metastatic colorectal cancer. Tumour microenvironment plasticity confers resistance to EGFR-targeted therapy. Cetuximab and panitumumab suppress tumours through ADCC mediated by NK cells and macrophages. Dysfunction of NK cells and macrophages with lower ADCC impairs the suppression of EGFR-targeted therapy in cancer. Reduced density of effector T cells and increased PD-L1 expression in cancer cells also promote survival from cancer. CAFs promote resistance to targeted therapy by secreting growth factors that activate the RAS or MET pathway. Abnormal angiogenesis always predicts poor response to anti-EGFR mAbs. Therapies focused on the microenvironment are also shown in the figure. Abbreviations: CAFs, cancer-associated fibroblasts; NK cells, natural killer cells; ADCC, antibody-dependent cellular cytotoxicity; PD-1, programmed death 1; PD-L1, programmed death ligand 1. VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor