Mechanisms of resistance to anti-epidermal growth factor receptor inhibitors in metastatic colorectal cancer

Figure 1 Epidermal growth factor receptor and its downstream signaling pathway. Binding of ligands such as epidermal growth factor (EGF) to Epidermal growth factor receptor (EGFR) activates downstream Ras/ERK and PI3K/Akt pathways and regulates various physiological processes. The anti-EGFR monoclonal antibodies (mAbs) cetuximab and panitumumab block the activation of these pathways.

Figure 2 Mechanisms of resistance to anti-epidermal growth factor receptor monoclonal antibodies in metastatic colorectal cancer. A: Activating mutations of EGFR effectors, such as RAS, BRAF and PI3KCA, or PTEN loss of function, cause persistent activation of downstream signaling regardless of EGFR inhibition; B: Mutations in extracellular domain of EGFR inhibit cetuximab binding, but not panitumumab, mediating acquired resistance. Mutations in kinase domain of EGFR led pathways activation in the context of acquired resistance; C: Amplification/activation of alternative receptors such as HER2 or MET, can bypass the EGFR blockade and mediate pathways activation. EGFR: Epidermal growth factor receptor.