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Review
. 2015 Sep;5(5):390-401.
doi: 10.1016/j.apsb.2015.07.001. Epub 2015 Jul 26.

Mechanisms of resistance to EGFR tyrosine kinase inhibitors

Lihua Huang  1 , Liwu Fu  1
Affiliations
Review

Mechanisms of resistance to EGFR tyrosine kinase inhibitors

Lihua Huang et al. Acta Pharm Sin B. 2015 Sep.

Abstract

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.

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Figures

None
Graphical abstract
Figure 1
Figure 1
EGFR and its signal pathway. There is subsequent autophosphorylation of the cytoplasmic tyrosine kinase domain, which, with the aid of adapter proteins (e.g., SHC and GRB-2), triggers downstream signaling. The principal pathways included: (1) RAS/RAF/MEK, (2) PI3K/AKT and (3) JAK/STAT pathways.
Figure 2
Figure 2
Aberration of HER families. Members of HER families get involved in the resistance to EGFR-TKIs. The secondary mutations of EGFR, EGFR-vIII, the overexpression of HER2 or mutations of HER2 contribute to the resistance in the presence of EGFR-TKIs. Compared to the other HER proteins, there are currently no mutational alterations known to confer oncogenic activities to HER3. In most cases, HER3 phosphorylation is driven by one of HER family kinase partners, like HER1 and HER2. What׳s more, resistance can also occur through amplification of the proto-oncogene c-Met and the c-Met-mediated phosphorylation of HER3. HER3 serves as a key activator of downstream PI3K/AKT and MEK/MAPK signal pathways through dimerization with other HER family proteins or other molecules.
Figure 3
Figure 3
Synchronous activation of redundant kinases and abnormality of the downstream pathway.
Figure 4
Figure 4
Apoptosis pathway mediated by BIM.
Figure 5
Figure 5
The potential targets for the relative treatment to overcome the resistance to EGFR-TKIs.
See this image and copyright information in PMC

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References

    1. Ciardiello F., Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358:1160–1174. - PubMed
    1. Bethune G., Bethune D., Ridgway N., Xu Z. Epidermal growth factor receptor (EGFR) in lung cancer: an overview and update. J Thorac Dis. 2010;2:48–51. - PMC - PubMed
    1. Yu H.A., Arcila M.E., Rekhtman N., Sima C.S., Zakowski M.F., Pao W. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240–2247. - PMC - PubMed
    1. Kobayashi S., Boggon T.J., Dayaram T., Jänne P.A., Kocher O., Meyerson M. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786–792. - PubMed
    1. Yun C.H., Mengwasser K.E., Toms A.V., Woo M.S., Greulich H., Wong K.K. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008;105:2070–2075. - PMC - PubMed