Tuberc Respir Dis.  2013 Nov;75(5):188-198.

Molecular Basis of Drug Resistance: Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and Anaplastic Lymphoma Kinase Inhibitors

• Yang SH

Abstract

Over the past decade, several kinase inhibitors have been approved based on their clinical benefit in cancer patients. Unfortunately, in many cases, patients develop resistance to these agents via secondary mutations and alternative mechanisms. To date, several major mechanisms of acquired resistance, such as secondary mutation of the epidermal growth factor receptor (EGFR) gene, amplification of the MET gene and overexpression of hepatocyte growth factor, have been reported. This review describes the recent findings on the mechanisms of primary and acquired resistance to EGFR tyrosine kinase inhibitors and acquired resistance to anaplastic lymphoma kinase inhibitors, primarily focusing on non-small cell lung carcinoma.

Keyword

Drug Resistance; Protein Kinase Inhibitors; Receptor, Epidermal Growth Factor; Receptor Protein-Tyrosine Kinases

MeSH Terms

Drug Resistance*
Epidermal Growth Factor*
Hepatocyte Growth Factor
Humans
Lung
Lymphoma*
Phosphotransferases*
Protein Kinase Inhibitors
Protein-Tyrosine Kinases
Receptor Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor*
Epidermal Growth Factor
Hepatocyte Growth Factor
Phosphotransferases
Protein Kinase Inhibitors
Protein-Tyrosine Kinases
Receptor Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor

Figure

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  Figure 1 The mechanism of primary resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). The activation of EGFR downstream molecules and other ErbB family member receptor tyrosine kinases bypasses the inhibition of EGFR signaling via EGFR-TKIs and also induces primary resistance to EGFR-TKIs. PI3K: phosphoinositide 3-kinase; PTEN: phosphatase and tensin homolog. This figure is reprinted from the article by Nakata A and Gotoh N6.

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  Figure 2 Selected 1st, 2nd and 3rd generation epidermal growth factor receptor (EGFR) inhibitors for non-small cell lung carcinoma. This figure is reprinted from the article by Giroux S24.

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  Figure 3 (A) Erlotinib bound to the epidermal growth factor receptor (EGFR) tyrosine kinase, the gatekeeper residue (T790) is highlighted in green; cysteine-797, which forms a covalent bond with 2nd and 3rd generation irreversible EGFR inhibitors, is highlighted in green. (B) Structure of WZ-4002 covalently bound to EGFR T790M via cysteine-797. This figure is reprinted from the article by Giroux S24.

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  Figure 4 The mechanism of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). The secondary T790M mutation of EGFR leads to a decrease in the affinity to EGFR-TKIs. MET or insulin growth factor receptor (IGFR) activation induces the activation of phosphoinositide 3-kinase (PI3K)/Akt pathway independent of EGFR activation. HGF: hepatocyte growth factor; PTEN: phosphatase and tensin homolog; IGF: insulin growth factor. This figure is reprinted from the article by Nakata A and Gotoh N6.

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  Figure 5 Representative chemical structures of c-MET and heat shock protein 90 inhibitors given in combination with epidermal growth factor receptor inhibitors in non-small cell lung carcinoma patients. This figure is reprinted from the article by Giroux S24.

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  Figure 6 Prevalence of acquired drug resistance mechanisms. This pie chart illustrates the frequency of observed mechanisms of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in 37 patients with non-small cell lung carcinoma, who were biopsied at the time of acquired resistance. Amp: amplification; PIK3CA: phosphatidylinositol-3-kinase catalytic subunit; SCLC: small-cell lung cancer. This figure is reprinted from the article by Sequist LV et al.28.

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  Figure 7 Crizotinib bound to the anaplastic lymphoma kinase domain with locations of secondary mutations known to confer acquired resistance, highlighted in green. This figure is reprinted from the article by Giroux S24.

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  Figure 8 Ligand-triggered resistance to epidermal growth factor receptor (EGFR) inhibitors and anaplastic lymphoma kinase (ALK) inhibitors. In EML4-ALK lung cancer cells, EGFR ligands activate EGFR and downstream phosphoinositide 3-kinase/Akt and ERK1/2 pathways and also triggers resistance to crizotinib. EGF: epidermal growth factor; TGF-α: transforming growth factor-α; WT: wild type. This figure is reprinted from the article by Yano S et al.55.

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