Figure 3.
Mechanisms of resistance to EGFR TKIs. a | A mutant form of EGFR termed EGFRvIII has an in-frame deletion mutation that produces a truncated 150 kDa protein, which is constitutively phosphorylated in a ligand-independent manner.161 b | EGFR-dependent tumors that are initially sensitive to EGFR TKIs acquire a mutation at threonine 790. Substitution of this residue in EGFR with a bulky methionine may cause resistance by steric interference with binding of TKIs, including gefitinib and erlotinib.77–79 c | Tumors can become resistant when individual tumor cells undergo an oncogenic shift, which has been noted with several other RTKs, including HGF receptor,148 AXL and IGF1R. d | In addition to IGF1R as a mechanism of escape, downregulation of the IGF- binding proteins IGFBP3 and IGFBP4, have been implicated in resistance to TKIs. These proteins are crucial for regulating the levels of IGF1R ligands, and loss leads to overactivation of the receptor.152 e–f | Mutations in both PTEN and Ras have been implicated in impaired response to TKI therapy.134,135 g | Cells that developed acquired resistance to gefitinib in vivo were shown to have increased VEGF production leading to altered angiogenesis and enhanced escape from cetuximab therapy.116 h | VEGFR1 has also been implicated in the contribution to resistance to EGFR TKIs.120 Abbreviations: AXL, tyrosine-protein kinase receptor UFO (AXL oncogene); EGFR, epidermal growth factor receptor; HGF, hepatocyte growth factor; IGF1R, insulin-like growth factor 1 receptor; IGFBP, insulin-like growth factor-binding protein; kDa, kilodalton; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase; TKI, tyrosine kinase inhibitor, VEGF, vascular endothelial growth factor; VEGFR1, vascular endothelial growth factor receptor 1.