Since the discovery that non-small cell lung cancer (NSCLC) is driven by epidermal growth factor receptor (EGFR) mutations, the EGFR tyrosine kinase inhibitors (EGFR-TKIs, e.g., gefitinib and elrotinib) have been effectively used for clinical treatment. However, patients eventually develop drug resistance. Resistance to EGFR-TKIs is inevitable due to various mechanisms, such as the secondary mutation (T790M), activation of alternative pathways (c-Met, HGF, AXL), aberrance of the downstream pathways (K-RAS mutations, loss of PTEN), impairment of the EGFR-TKIs-mediated apoptosis pathway (BCL2-like 11/BIM deletion polymorphism), histologic transformation, ATP binding cassette (ABC) transporter effusion, etc. Here we review and summarize the known resistant mechanisms to EGFR-TKIs and provide potential targets for development of new therapeutic strategies.
Keywords: ABC, ATP binding cassette; ABCB1, ATP binding cassette, sub-family B, member 1; ABCC1, ATP binding cassette, sub-family C, member 1; ABCC10, ATP binding cassette, sub-family C, member 10; ABCG2, ATP binding cassette, sub-family G, member 2; AKT, protein kinase B; ALK, anaplastic lymphoma kinase; AXL, Anexelekto; BCL-2, B-cell CLL/lymphoma-2; BCL2L11/BIM, BCL2-like 11; BH3, BCL2-homology domain 3; BRAF, v-RAF murine sarcoma viral oncogene homolog B1; CML, chronic myelogenous leukemia; CRKL, Crk-like protein; EGFR; EGFR, epidermal growth factor receptor; EGFR-TKIs, epidermal growth factor receptor tyrosine kinase inhibitors; EGFRvIII, EGFR variant III; EML4, echinoderm microtubule-associated protein-like 4; EMT, epithelial mesenchymal transition; ERK1/2, extracellular signal-regulated kinases; FGFRs, fibroblast growth factor receptors; FGFs, fibroblast growth factors; GAS6, growth-arrest-specific protein 6; HER, human epidermal receptor; HGF, hepatocyte growth factor; IGF, insulin growth factor; IGF-1R, IGF-1 receptor; IGFBPs, IGF-binding proteins; IL, interleukin; IL-6R, IL-6 receptor; JAK, janus kinase; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase; Mechanisms; NSCLC, non-small cell lung cancer; PDGFRs, platelet-derived growth factor receptors; PDGFs, platelet-derived growth factors; PI3K, phosphatidylinositol-3-kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase,catalytic subunit alpha; PTEN, phosphatase and tensin homolog; RAF, rapidly accelerated fibrosarcoma; RAS, rat sarcoma; RTK, tyrosine kinase receptor; Resistance; SF, scatter factor; SOCS3, suppressor of cytokine signaling 3; STAT, signal transducers and activators of transcription; TKIs; TKIs, tyrosine kinase inhibitors; TKs, tyrosine kinases; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.